NSAIDs are some of the most commonly used over-the-counter pain medications, including ibuprofen, aspirin, naproxen, and prescription versions such as diclofenac, among others. They work by inhibiting inflammation, and are thus generally used for inflammatory pain.

But like all medications, NSAIDs interrupt a bodily process with a specific, important function. In this case, the function they interrupt is inflammation. We tend to think of “inflammation” as a root cause of illness in and of itself, but it isn’t. Inflammation is your body’s attempt to fix a problem, or fight against a foreign invader. Suppressing the process interferes with the body’s attempt to self-heal. Not only that, but since so many biochemical pathways are interconnected, if you interfere with one, you’ll inevitably cause a disturbance somewhere else (that’s what side effects are).

Serious problems from NSAIDs are relatively common. NSAIDs are responsible for some 30% of all hospital visits due to adverse drug reactions.

NSAIDs and Your Mitochondria

Your mitochondria are the powerhouses of all of your cells (except red blood cells, which don’t have any). The mitochondria take the electrons and protons from your food, water, and air, and turn them into ATP, your body’s energy currency. Any disruption to this process would naturally have very wide-ranging consequences.

Unfortunately, NSAIDs cause damage to Complex I in the Electron Transport Chain, the final step inside the mitochondria leading to ATP production. The worst offender of the NSAIDs for this is diclofenac, but the other NSAIDs will inhibit Complex I as well.

This means not only will ATP production be hindered (and thus energy supply will be lower), but because the electrons going into the chain won’t be able to complete the process, they will instead leak out into the mitochondria, producing reactive oxygen species and oxidative damage. When such damage accumulates, it ultimately leads to apoptosis, or programmed cell death.

This is one of the primary theories for how NSAIDs cause damage to multiple organs.

NSAIDs and Your Gut

Perhaps the best known side effect of NSAIDs has to do with damage to the stomach and intestinal lining, particularly ulcers. Visible damage to the stomach or intestinal lining can be found in about 71% of chronic NSAID users.

The mechanism for how this occurs is still not fully understood. The mitochondrial damage mentioned above is implicated as one possible mechanism.

NSAIDs also are believed to react with the lipid bilayer that protects the mucosa in the gut, rendering it less protective against gastric acid.

Finally, and ironically, NSAIDs (which stands for non-steroidal anti-inflammatory drugs), actually trigger release of multiple pro-inflammatory cytokines in the gastric mucosa.

The body is always trying to seek balance. Suppress a natural process, and you will eventually get a rebound in the opposite direction. (This is actually the principle upon which homeopathy is based.)

NSAIDs, Your Heart and Cardiovascular System

Many individuals take a baby aspirin (an NSAID) in order to prevent clotting and protect them from heart attack or stroke. While low dose aspirin does indeed prevent clotting, at a dose apparently too low to trigger adverse reactions, that is not the case for other, full-strength NSAIDs.

The high metabolic activity of cardiac cells requires a great deal of energy, or ATP, generated by the mitochondria. NSAIDs generally inhibit Complex I in the Electron Transport Chain, so this is one way in which the heart may be compromised by these drugs.

However, NSAIDs may affect the mitochondria of the heart in another way as well. The primary mechanism of action of NSAIDs is to suppress production of pro-inflammatory prostaglandins. Because the upstream compound is another inflammatory fatty acid called arachidonic acid, it accumulates (see the pathway here). Arachidonic acid inhibits both Complex I and Complex III of the Electron Transport Chain, which greatly accelerates the process of apoptosis, or programmed cell death.

NSAIDs usually inhibit two COX enzymes: 1 and 2. Second generation NSAIDs, with the suffix -coxib, specifically inhibit COX-2, and not COX-1. These tend to spare the gut from the side effects mentioned above, but they also lose the balancing effect on clotting risks between the two enzymes, and can thus increase risk for clotting. Since it certainly appears that clotting is the primary risk factor for heart disease, this is a big deal. This effect was why Vioxx, a second generation NSAID, was withdrawn from the market in 2004.

NSAIDs and Your Kidneys

NSAIDs are also commonly associated with renal damage. This is because their primary mechanism of action, blocking prostaglandins, ignores the fact that prostaglandins have a positive function: they dilate the blood vessels in the kidneys. Decreased perfusion to the kidneys can lead to acute kidney injury.

Additionally, decreased prostaglandin levels and the accompanying decreased blood flow can lead to sodium retention (because it’s the kidneys that regulate electrolyte levels). Water follows sodium, so increased sodium can lead to edema as well as hypertension.

If the kidneys are already damaged, the resulting increase in fluid can eventually lead to heart failure.

NSAIDs and Chronic Pain

If all that weren’t enough, there’s still the rebound problem: your body produces inflammation in response to acute injury in order to trigger healing. If you suppress that process, you’re much less likely to heal effectively.

A recent study showed that those who take anti-inflammatories early in acute injury may receive initial relief, but are more likely to end up with chronic pain down the line.

The Upshot

There is a time and a place for pain medication, but I believe they are used far more regularly and casually than they should be. Given their easy accessibility, we may forget that these are powerful drugs with potentially serious consequences. NSAIDs should be used only when absolutely needed, and as sparingly as possible.