NSAIDs and Black Box Warnings

One of the terms in the pharmaceutical industry is the “Black Box Warning”. What is it and why is it so important for each of us? In this article, I will try to understand the critical importance of this warning, especially in relation to nonsteroidal anti-inflammatory drugs (NSAIDs).

A “black-box warning” is the highest level of warning about serious side effects of a medical drug. The importance of this warning cannot be overstated – it is a clear indication from a regulatory body of potentially serious consequences of using a particular drug. In the United States, such a stern warning is issued by the FDA.

Drugs that carry a “black box warning” are diverse, covering many different classes of medications. However, for the purpose of this discussion, we will focus on a particular group of medications commonly known as nonsteroidal anti-inflammatory drugs (NSAIDs). This group includes such well-known names as Nurofen, Ibuprofen, Aspirin, Naproxen, Diclofenac (the strongest one) and others. There is also a group of medications containing acetaminophen, such as Calpol and Tylenol.

How do these medications work? Simplistically, nonsteroidal anti-inflammatory drugs block two specific enzymes (COX1 and COX2) that produce lipids called prostaglandins. The role of prostaglandins in our body is diverse and critically important. They participate in many processes in our GI tract, kidneys, vascular system, and more, performing vital functions. Prostaglandins also play a key role in transmitting pain, inflammation, and fever signals, which are the body’s response to disruptions caused by viral or bacterial attack or physical tissue damage.

When taking nonsteroidal anti-inflammatory drugs, they interfere with these processes, suppressing the production of prostaglandins. This can be useful for reducing pain and inflammation, but it can lead to serious side effects, which is why such drugs carry a “black-box warning”. These side effects can vary from problems with the gastrointestinal tract to an increased risk of cardiovascular diseases.

The primary function of these medications is to “mute” the pain signal, which is a kind of malfunction indicator sent by our body. With this come two substantial issues that it’s important to pay attention to.

First, by using these drugs, we deprive the body of the ability to independently identify and respond to detected disruptions. This means that we are effectively allowing the problem or source of pain to “operate with impunity”, continuing to potentially harm our body.

Second, when using NSAIDs, we run the risk of blocking vital body functions. Prostaglandins, produced by the enzymes COX1 and COX2, are responsible for many key processes in our body. So, when we interrupt their production, we stop these important functions.

Let’s consider an example: the use of NSAIDs can significantly increase the risk of developing a stomach ulcer. According to medical research, people taking these drugs have a 5-fold increased risk of developing an ulcer. Prostaglandins formed by the enzyme COX1 play an important role in protecting the gastric mucosa from digestive juices. By blocking the action of these important molecules, we allow digestive juices to “digest” the walls of our own stomach.

This can lead to serious problems, especially considering that some NSAIDs also have a blood-thinning effect. As a result, significant blood loss can occur if an ulcer develops. For instance, research shows that in patients taking NSAIDs, the risk of bleeding from an ulcer can be up to 15% higher compared to those who do not take these drugs.

Moreover, there are other consequences of long-term use of NSAIDs, including an increased risk of cardiovascular diseases and kidney failure. For example, according to a study published in the “New England Journal of Medicine”, the risk of heart attack or stroke may increase by 20-50% in people taking NSAIDs for a long time. Similarly, research shows that long-term use of NSAIDs can more than double the risk of chronic kidney failure.

In this context, it is especially important to discuss with your doctor the potential risks and benefits of using NSAIDs in your particular case. It is necessary to take into account possible side effects and evaluate them in the context of your health condition and the potential benefit from pain or inflammation relief.

Lastly, it’s worth noting that not all NSAIDs affect the body in the same way. For example, some of them, such as ibuprofen, are more likely to affect COX-2, and their use may come with a lower risk of side effects associated with COX-1, like stomach ulcers.

Prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) can cause micro-perforation of the intestinal walls, which creates certain health problems. In this case, insufficiently digested food compounds can enter the blood and lymph. The immune system, not recognizing these particles, responds with an inflammatory reaction. Over time, such uncontrolled activity of the immune system can lead to the development of autoimmune diseases. Leading experts estimate that up to 70% of autoimmune diseases may be associated with problems in the intestine, including damage caused by NSAIDs.

There is a quite noticeable correlation between taking high doses of NSAIDs and the risk of developing cardiovascular diseases. According to data published in the Lancet journal, a person who takes large doses of NSAIDs increases the risk of developing cardiovascular diseases by 30%. For instance, in people who have survived a heart attack and continue to take these drugs, the risk of sudden death increases by 60%, and the risk of a recurrent heart attack – by 30%, as noted in the Circulation journal.

Despite the fact that NSAIDs are often used to alleviate arthritic symptoms and that they may initially alleviate inflammation and pain, in the long term they can only exacerbate the pathology. In one study published in the Journal of Rheumatology, it was found that the use of NSAIDs may accelerate joint wear, increasing the progression of arthritis.

Another noticeable negative effect from the use of NSAIDs is related to bone injuries. Taking NSAIDs soon after a fracture can disrupt the normal process of bone tissue regeneration. As a result, the bone fusion process may be inadequate, creating conditions for further complications, including chronic pain and impaired functionality of the corresponding limb.

Moreover, patients do not always receive all the necessary information about the possible risks of using NSAIDs. In the UK, for example, pharmacists and doctors were given a warning in September 2016 about the high risk of severe complications or even fatal outcomes when using ibuprofen in cases of “chickenpox”. It is believed that the drug stimulates the virus’s penetration into deeper layers of the skin and increases the risk of severe infectious neurosis, up to a lethal outcome. However, this information is typically not indicated in the leaflet accompanying the medication, and the patient remains unaware of the potential risks.

Aspirin (also known as acetylsalicylic acid) is also an NSAID, but it is generally considered the safest NSAID when used in low doses (between 75 to 100 mg per day, which may be not enough for pain relief). It has anti-inflammatory, antipyretic and analgesic properties. Additionally, aspirin is widely used to prevent cardiovascular diseases due to its ability to thin the blood and prevent blood clot formation.

David Sinclair, a professor at Harvard University, who studies the biology of aging, besides a range of other drugs, regularly takes low doses of aspirin. According to him, aspirin can help prevent a range of chronic diseases, including cardiovascular diseases, which in turn may contribute to life extension. This is related to its anti-inflammatory properties and its ability to prevent the formation of blood clots. However, despite the possible benefits, aspirin intake is also associated with a risk of side effects, including gastrointestinal problems and bleeding. Specifically, long-term use of aspirin, even in low doses, can increase the risk of stomach ulcers and bleeding.

Regarding alternatives to NSAIDs, there are several possibilities that may be helpful depending on the specific type of inflammation. For example, paracetamol. Paracetamol is not a NSAID. It is an analgesic (pain reliever) and antipyretic (fever reducer). While it can relieve symptoms of many of the same conditions that NSAIDs treat (like headache, toothache, or fever), paracetamol does not have the same anti-inflammatory property as NSAIDs.

In folk medicine, arnica is often used to alleviate pain and inflammation. Turmeric, known for its anti-inflammatory properties, can be beneficial for certain inflammatory conditions. Yarrow, boswellia, bromelain, and ginger are also considered as potential natural anti-inflammatory agents.