Updated: Oct 19, 2018
By Dr. Andrew Cummins
Before reading the rest of this article I want you to think about this one statement: Inflammation is the immune system’s response to infection and/or injury.
If there is chronic inflammation in the body where is the infection, where is the injury, or where are both? When there is an infection or injury in the body the immune system responds by producing inflammatory chemicals. The reason for this is to eliminate the infection or to repair the damage from the injury. Once the infection is removed and the damage is repaired by the inflammatory process, the immune system can lessen the production of the inflammatory chemicals and we stop feeling the pain.
The problem is when the inflammatory process continues and the immune system constantly produces inflammatory chemicals. These inflammatory chemicals are constantly stimulating nerves creating the symptoms of pain and stiffness.
This continued inflammatory process not only causes constant pain, but it can eventually damage tissue and change the structure and function of the body. We see this with Ankylosing Spondylitis and other forms of Spondyloarthrits with reduced function, impaired mobility, and altered posture.
The question is why is the inflammatory process continuing? Why is there constant inflammation being produced that causes pain and stiffness? As I stated in the beginning, inflammation is the immune system’s response to infection and/or injury.
When we have a chronic inflammatory process such as with Ankylosing Spondylitis and other forms of Spondyloarthritis, the immune system is imbalanced and is constantly reacting to an infection and/or is constantly trying to repair damage. The problem with chronic inflammation is that the inflammatory response can cause even more damage.
The pain and inflammation are signals that there is a problem in the body that needs to be taken care of. Both tell us that something needs to be eliminated or put into balance such as our gut bacteria and that something needs to be repaired or supported and stabilized such as the spine and other joints. The suppression of this inflammation and pain without addressing the real problem can cause additional dysfunction in the human body.
Non-steroidal anti-inflammatory drugs are usually the first line of treatment for the pain and stiffness associated with Ankylosing Spondylitis and other forms of Spondyloarthritis. The recommendation in the medical literature is to prescribe the lowest effective dose for the shortest period of time possible to minimize the side effects of these drugs.
Unfortunately because of the chronic pain and stiffness associated with AS these drugs are usually prescribed at higher doses and need to be taken for an extended period of time, sometimes for the rest of an individual’s life.
Two of the main areas of the body affected by NSAIDs are the gastrointestinal tract and the cardiovascular system. In addition to the gut and the heart, the kidneys, liver, and lungs can be affected as well.
In this article I will focus on the side effects NSAIDs have on the gut and the heart. All non-steroidal anti-inflammatory drugs including Diclofenac, Meloxicam, Indomethacin, Celebrex, Ibuprofen, Naproxen, and Aspirin affect one or both of these areas of the body. COX-2 inhibitors were designed to avoid gastrointestinal side effects, but the medical literature shows that the selective COX-2 inhibitor Celebrex and semi-selective COX-2 inhibitor Meloxicam damage the gut as well. The reason is because the COX-2 enzyme is also important for the protection and health of the gut lining.
The premise of using NSAIDs is that these drugs reduce the chronic inflammation of Ankylosing Spondylitis and other forms of Spondylitis and therefore reduce the symptoms of pain and stiffness. As my previous article pointed out https://www.drcumminswellness.com/blog/ankylosing-spondylitis-and-spinal-fusion-factors-that-may-prevent-or-slow-this-process-part-2, high levels of harmful bacteria, low levels of good bacteria, toxins, undigested food particles, a leaky gut, and damage to the joints of the spine from poor posture, excessive sitting, and weak back and gluteal muscles are what lead to the inflammation to begin with.
I re-emphasize that point because a lack of NSAIDs isn’t the cause of the chronic inflammation, pain, and stiffness associated with Ankylosing Spondylitis. The first line of treatment that can cause serious side effects isn’t addressing the root of the issue. This requires a shift in thinking and a new paradigm that isn’t focused on symptom suppression, but on addressing the root cause of the problem.
In the case of Ankylosing Spondylitis the root cause of the problem is a spinal structural issue from the factors above combined with intestinal permeability, gut inflammation, and dysbiosis, low levels of good bacteria combined with high levels of harmful bacteria. No matter how much the inflammation is suppressed with drugs the inflammation will never stop being produced unless the root issues are addressed.
I like to use the following analogy with my clients and patients. Imagine that the faucet of a sink is turned on and the drain is clogged. Eventually the water in the sink is going to run over and start to spill onto the floor. To prevent the water from getting on the floor you put a bucket on the floor underneath the sink to catch the water. Eventually the water will fill the bucket and run onto the floor. The problem isn’t going to be solved until the faucet is turned off to stop the running water.
Addressing the structural issues that damage the spine and correcting the gut inflammation and dysbiosis that creates the chronic inflammation represents turning the faucet off. The non-steroidal anti-inflammatory drugs represent the bucket. The sad irony is that NSAIDs in and of themselves will contribute to the ongoing chronic inflammation they are supposed to suppress because of the damage NSAIDs do to the gut lining.
NSAIDs Suppress Inflammation and Mucus Production
Non-steroidal anti-inflammatory drugs reduce pain and stiffness because of reducing inflammatory chemicals in the body called prostaglandins. When prostaglandins stimulate nerves we feel the pain. The problem with suppressing prostaglandin production in the body is that prostaglandins do more than just contribute to increased inflammation and pain.
It’s essential to understand that prostaglandins have many important functions in the body. Prostaglandins help intestinal cells of the gut lining repair, stimulate blood flow to help heal tissues, contribute to normal reproductive health, regulate blood pressure in the kidneys, and even help balance and resolve the inflammatory process.
One of the most important effects of prostaglandins is the stimulation of mucus production on the lining of the gut. This is why there will be gastrointestinal bleeding and ulcers with the use of non-steroidal anti-inflammatory drugs such as Ibuprofen, Naproxen, Aspirin, Diclofenac, Indomethacin, and Meloxicam.
As previously mentioned, Celebrex is an NSAID that was designed to lessen the harmful effects on the gut, but as the medical literature points out this COX-2 inhibitor causes damage to the gut lining as well, especially to the small intestine.
In addition, once the gut lining has been damaged the COX-2 enzyme is important in producing prostaglandins that help renew and repair the damaged intestinal cells. Once the cells of the gut lining have been damaged by bacteria, toxins, undigested food particles and NSAIDs, the intestinal cells must be replaced and renewed with new cells. When NSAIDs inhibit the COX-2 enzyme to reduce prostaglandins to decrease inflammation and pain, the process of repair and healing to the damaged gut lining cannot take place.
It is important to re-emphasize the point that the only thing separating the contents in the gut such as bacteria, food, and toxins from the inside of our body and gut immune system is our gut lining that is a very delicate barrier that is one cell layer thick.
One of the most important factors protecting the gut lining is the mucus layer that sits on top of our intestinal cells.
The lining of the stomach and large intestine have two layers of mucus sitting on top of intestinal cells, but the small intestine only has one layer of mucus protecting the cells of the gut lining. This makes the intestinal cells of the small intestine much more vulnerable to damage from bacteria, toxins, and undigested food particles.
Harmful bacteria cause damage to the gut lining and cause intestinal inflammation by attaching to the gut wall. The mucus that sits on top of the gut lining separates the intestinal cells from harmful bacteria. When NSAIDs block the production of prostaglandins to reduce inflammation and pain, this also reduces the production of mucus that protects the intestinal cells from harmful bacteria.
Another very important function of our small intestinal cells is the absorption of nutrients. When harmful bacteria attach to the gut lining because of a reduction in mucus production this causes inflammation in the gut. When there is inflammation in the gut this causes damage to the cells of the small intestine that absorb nutrients.
When these cells are damaged there is malabsorption of nutrients and protein loss. This inflammation and damage to the cells of the gut lining can also lead to bleeding and ulcers. This damage can occur in the stomach, small intestine, and large intestine.
Small intestinal cells also produce enzymes that help break down food. These cells also produce a hormone that stimulates the pancreas to produce digestive enzymes and the gallbladder to release bile. These digestive enzymes and bile are extremely important for proper digestion and absorption of food and nutrients. When the gut lining of the small intestine is damaged from non-steroidal anti-inflammatory drugs this can greatly reduce the digestive process and lead to the malabsorption of crucial nutrients.
Also, undigested food particles from impaired digestion can cause additional damage to the gut lining, causing an immune reaction leading to more chronic inflammation. In addition, undigested food particles in the gut can feed harmful bacteria leading to the symptoms of Small Intestinal Bacterial Overgrowth such as gas, bloating, constipation, abdominal discomfort, or diarrhea.
NSAIDs Increase TNF-alpha
We know that the inflammatory chemical TNF-alpha is also partly responsible for the inflammation and pain of AS and is the target of biologic drugs such as Humira, Enbrel, and Remicade.
It is important to understand that prostaglandins inhibit the production of TNF-alpha. So when you block the production of prostaglandins with NSAIDs this will increase the production of TNF-alpha.
NSAIDs Damage Intestinal Cells and Cause Leaky Gut
From the previous article https://www.drcumminswellness.com/blog/ankylosing-spondylitis-and-spinal-fusion-factors-that-may-prevent-or-slow-this-process-part-2 it was discussed that certain bacterial toxins such as lipopolysaccharide, LPS can interact with the immune system in the gut and that this interaction can lead to inflammation throughout the body.
This interaction between bacterial toxins and the gut immune system can also cause inflammation in the gut itself. It was also discussed that a leaky gut allows the bacterial toxins to easily come in contact with the gut immune system.
So how do non-steroidal anti-inflammatory drugs damage intestinal cells and cause a leaky gut? In addition to decreasing prostaglandins and mucus production on the gut lining, NSAIDs cause damage to the mitochondria inside the intestinal cells. Mitochondria are like engines inside of cells that produce energy for the cell. Mitochondria are what keep a cell alive and if the mitochondria are damaged then the cell will die.
NSAIDs directly damage mitochondria and this creates an excessive amount of reactive oxygen species. Too many reactive oxygen species will damage and destroy cells and tissues in the body. These reactive oxygen species also damage the mitochondria even further. Once the mitochondria are damaged this affects the tight junctions between the cells of the gut lining and this leads to intestinal permeability, better known as leaky gut.
When bacterial toxins interact with the gut immune system this leads to chronic inflammation in the gut. This results in more cells of the immune system such as neutrophils to come into the cells of the gut. These immune system cells secrete reactive oxygen species and this causes further damage to the cells of the gut lining.
To summarize this process, NSAIDs reduce prostaglandins which reduces inflammation and pain. In addition to creating inflammation and pain, prostaglandins stimulate mucus production on the lining of the gut. Mucus on the gut lining is extremely important for the health of intestinal cells.
Mucus keeps harmful bacteria and toxins from attaching to and penetrating the cells of the gut lining. Mucus on the gut lining nourishes the intestinal cells keeping the gut lining healthy and strong preventing a leaky gut. In the process of reducing prostaglandins, NSAIDs reduce mucus production on the lining of the gut.
This exposes the intestinal cells to bacteria and bacterial toxins which damages the cells of the gut. NSAIDs also damage mitochondria inside of the intestinal cells and this process destroys the cell and the tight junctions between the intestinal cells leading to a leaky gut.
NSAIDs and PPIs Contribute to SIBO
Proton pump inhibitors such as Omeprazole and H2 blockers such as Pepcid are commonly given along with non-steroidal anti-inflammatory drugs to decrease stomach acid and to lessen the damage to the lining of the stomach.
It is important to understand that stomach acid reduces levels of harmful bacteria such as gram-negative bacteria that produce the toxin LPS. Proton pump inhibitors increase the level of these harmful bacteria and contribute to bacterial overgrowth in the small intestine. PPI’s not only cause an overgrowth of harmful bacteria, but can also decrease levels of beneficial bacteria.
This process of small intestinal bacterial overgrowth, better known as SIBO, contributes to the digestive symptoms of bloating, constipation, gas, diarrhea, and the chronic inflammatory process of Ankylosing Spondylitis and other forms of Spondyloarthritis. In addition, NSAIDs also cause an imbalance in gut bacteria and contribute to an increase in harmful bacteria such as gram-negative bacteria that secrete the toxin LPS.
NSAIDs alone or in combination with acid suppressing drugs can lead to the process of not only digestive problems from SIBO, but also to increasing levels of harmful bacteria leading to chronic inflammation that attacks the joints leading to pain and stiffness.
NSAIDs Increase Heart Attack and Stroke Risk
As mentioned above, non-steroidal anti-inflammatory drugs reduce prostaglandins in the body which reduces inflammation and pain. Unfortunately when prostaglandins are reduced by NSAIDs this affects much more than just inflammation and pain.
So how do NSAIDs reduce prostaglandins that reduce inflammation and pain? In our cell membranes there is a fatty acid called arachidonic acid. During normal physiology and during times of inflammation from an infection or injury such as tissue damage, arachidonic acid is converted into prostaglandins and other chemicals by cyclooxygenase enzymes called COX-1 and COX-2. NSAIDs inhibit the COX-1 and COX-2 enzymes and this inhibits the formation of prostaglandins which reduces inflammation and pain.
As mentioned above, prostaglandins do more than produce inflammation and pain. Some prostaglandins dilate blood vessels and reduce the clotting of blood. Another chemical produced by the COX-1 enzyme called thromboxane A2 leads to constriction or narrowing of blood vessels and to increased blood clotting.
As you can see prostaglandins and other chemicals produced by the COX enzymes can have opposing actions in the body. Some prostaglandins cause blood vessels to dilate and reduce blood clotting and other chemicals produced by the COX enzymes cause blood vessels to constrict and increase blood clotting.
So if you inhibit the production of prostaglandins that cause blood vessels to dilate and decrease blood clotting and the chemicals that cause blood vessels to constrict and cause blood clotting are not inhibited, you could have a real problem.
This process happens especially with the selective COX-2 inhibitor Celebrex and the semi-selective COX-2 inhibitor Meloxicam. The problem is when you block the COX-2 enzyme without blocking the COX-1 enzyme you get an increased risk of heart attack and stroke. As mentioned above, this process causes blood vessels to constrict and blood more likely to clot.
As discussed in the section on the gut, Celebrex and Meloxicam have been found to damage the gut lining as well leading to leaky gut, ulcers, and GI bleeding.
NSAIDs Damage the Heart Muscle
Non-steroidal anti-inflammatory drugs such as Ibuprofen, Naproxen, Indomethacin, Diclofenac, Meloxicam, and Celebrex directly damage mitochondria in heart muscle cells. Mitochondria produce energy inside of cells and are essential to cell survival. When mitochondria are damaged, energy production dramatically decreases and the cell can die. When cells die, tissues and organs become damaged.
This process is the reason NSAIDs such as Celebrex, Meloxicam, Diclofenac, Indomethacin, Ibuprofen, and Naproxen are associated with the risk of heart failure. Most individuals think of heart attacks, when blood flow to the heart is interrupted from a blood clot when hearing about cardiovascular disease, but heart failure is a major cause of disability and death.
Heart muscle cells have thousands of mitochondria in each cell. Mitochondria provide the energy the heart needs to pump blood throughout the body 24 hours a day. When non-steroidal anti-inflammatory drugs damage mitochondria this increases reactive oxygen species in heart muscle cells. Excessive reactive oxygen species create oxidative stress and this process damages the cells and eventually the heart muscle itself.
When the mitochondria inside heart muscle cells are damaged the heart muscle can’t keep up with the energy demands of the heart and the body. The heart muscle gradually gets weaker and eventually heart failure begins to develop.
NSAIDs Increase Blood Pressure and can Damage Blood Vessels
The damage non-steroidal anti-inflammatory drugs such as Ibuprofen, Naproxen, Indomethacin, Diclofenac, Meloxicam, and Celebrex do to mitochondria increasing levels of reactive oxygen species can also lead to endothelial dysfunction. Endothelial dysfunction is when blood vessels can become damaged.
The cells inside of the blood vessel wall produce nitric oxide. Nitric oxide is very important for the health of blood vessels and helps to relax blood vessels and reduces blood pressure. When there is increased levels of reactive oxygen species and oxidative stress from NSAIDs this causes a decrease in the production of nitric oxide.
When levels of nitric oxide decrease blood vessels can become damaged and blood vessels become more narrow leading to increased blood pressure. Also, when blood vessels become damaged this increases the risk of blood clotting which can increase the risk of heart attacks.
As mentioned, non-steroidal anti-inflammatory drugs reduce prostaglandins in the body which reduces inflammation and pain. In addition to increasing levels of inflammation and pain from infection or injury, prostaglandins also have an effect on the kidneys. Prostaglandins allow the kidneys to get rid of sodium and water. When prostaglandin production is blocked by NSAIDs the kidneys retain more sodium and water and this process increases blood pressure. Increased blood pressure can also damage blood vessels and the heart muscle.
It is important to understand that the cardiovascular risks of NSAIDs can occur in individuals with no history of heart disease and risks can begin within weeks or months of beginning an NSAID. The only exception is aspirin. The problem with aspirin is that it can damage the gut lining leading to a leaky gut and bleeding in the GI tract. Aspirin can also lead to bleeding in the brain.
As mentioned previously, to minimize the side effects associated with damage to the gut and cardiovascular risks, the recommendation in the medical literature is to take NSAIDs such as Ibuprofen, Naproxen, Indomethacin, Diclofenac, Meloxicam, and Celebrex at the lowest effective dose for the shortest time possible. Again, the problem is that most individuals with Ankylosing Spondylitis or other forms of Spondyloarthritis take NSAIDs for years and sometimes for the rest of their life. The medical literature also points out that alternative options other than NSAIDs are desperately needed to reduce inflammation and pain because of the risks associated with the use of these drugs.