Non-Allergic Angioedema

Angioedema is an acute, but temporary, swelling of the deeper layers of the skin. The non-allergic form of the condition develops, most often, as a reaction to certain medications.

The swelling can occur anywhere on the body, though the lips and the skin around the eyes are most frequently affected. Uncommonly, the tongue and the mucous membranes of the throat and mouth also may swell.

Symptoms of non-allergic angioedema

Non-allergic angioedema is characterized by swellings or large, smooth welts. Unlike other types of angioedema, non-allergic angioedema never appears along with hives or a rash. The swellings are restricted to the skin and mucosal linings and are generally not painful. When itching is present, it is typically not intense.

The swellings can appear days, weeks, or even months after the first dose of a drug, and can remain for up to five days.

Airway involvement is uncommon, but if swellings in the throat, mouth, and tongue are too large, they can block the passage of air. This is a life-threatening emergency and should be treated immediately.

Triggers of non-allergic angioedema

The drugs that cause non-allergic angioedema are called renin-angiotensin-aldosterone-system blockers (RAE blockers) and angiotensin-converting enzyme (ACE) inhibitors. These usually are prescribed to lower blood pressure and promote cardiovascular health.

They work by inhibiting or interfering with the kinin system, a group of proteins and signaling molecules that regulate blood pressure and inflammation. However, in some individuals, this also can trigger angioedema.

The relationship between bradykinin and angioedema

One of the molecules in the kinin system, bradykinin, is particularly important for non-allergic angioedema as it widens the small blood vessels in the deep layers of the skin. This lets fluid flow into those layers, causing the swelling.

The levels of activated bradykinin are controlled by angiotensin 2, an enzyme that breaks down bradykinin. When the production of this enzyme is stopped by an ACE inhibitor, bradykinin levels are allowed to rise. This helps to reduce blood pressure, but in rare cases, it also can cause the swelling found in non-allergic angioedema.

Treatment of non-allergic angioedema

The usual methods of treating other types of angioedema do not apply to non-allergic angioedema. For example, it does not respond effectively to allergy medications such as antihistamines, corticosteroids, and epinephrine (as in an EpiPen), or to non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen. In fact, NSAIDs can trigger or worsen the symptoms of non-allergic angioedema.

There are, however, some medications that can help. Icatibant, a drug used to treat hereditary angioedema, and concentrated C1-inhibitor, a natural protein involved in inflammation, have been used successfully for treating non-allergic angioedema.

The main way to treat this form of angioedema is to figure out what drug caused the reaction and then stop using it if possible. If ACE inhibitors are the trigger, angiotensin receptor blockers (ARB) are considered to be relatively safe alternatives. (Discontinuing drugs and finding alternative drugs always should be discussed with a medical professional for safety purposes.)

Because an EpiPen cannot be used to reduce the swelling quickly, immediate physical intervention is necessary if the swelling blocks the airway and becomes life-threatening. Artificial respiration such as cardiopulmonary resuscitation (CPR) is used here to keep the patient alive until swelling subsides enough to breathe on his own, or until mechanical ventialtion options become available.


Angioedema News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.