NSAIDs: Pick Your Poison

By Josh Bloom — Nov 01, 2024

In the U.S., six non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage pain and inflammation. While this drug class is widely relied upon, it is also associated with gastrointestinal and cardiovascular risks. However, not all NSAIDs are the same; here’s a look at their key similarities and differences.

Lots of choices, none perfect.

It's not easy being in pain these days. Tylenol is virtually useless, something you probably already know. Just in case, I reviewed its utility – lack thereof, really in 2017.

Opioids? Please. Although there are now legal efforts in the works to mitigate anti-opioid hysteria, the DEA and the medical community (at least most of it) continue to view these drugs as the lepers of the pharmaceutical world. Here is some "evidence" of this, although it's not rigorously scientific. A Google search of the term "opioid free" turned up, well I don't know how many hits, because Stupid Google no longer provides these numbers. Perhaps they're too busy trying to stuff more ads onto every page. Neither does Duckduckgo.

But Bing does; it gave 14 million hits. (I asked our awesome Research Associate Julie Kasel to look through all of them. She's not done yet.) Suffice it to say that opioid phobia is alive and well, unlike the pain patients who are denied these drugs.

Given that Tylenol doesn't do much and opioids remain largely unavailable the obvious choice for treating pain and inflammation are the non-steroidal anti-inflammatory drugs (NSAIDs). That's just fine if you're able to take them; they are usually quite effective. But many of us can't, largely due to side effects. They can be murder on your esophagus, stomach, and kidneys, and most of them increase the risk of heart attacks. They are essential but also flawed drugs.

However, not all NSAIDs are alike. There are significant differences in efficacy and side effects within the class. Let's take a look at the six (1) most commonly used NSAIDs and examine the plusses and minuses of each drug.

Aspirin

Positives

Aspirin (acetylsalicylic acid, ASA) is effective in relieving headaches, muscle pain, arthritis, and reducing fevers. It is also used in low doses to prevent cardiovascular events. Aspirin is the only NSAID with antiplatelet properties, making it potentially useful in preventing blood clots that can cause heart attacks and strokes.

Negatives

Things are a bit more complicated here. Aside from gastrointestinal (GI) irritation, aspirin can cause GI bleeding and ulcers. This is why the American Heart Association does not recommend using the drug for the primary prevention of cardiovascular (CV) events in people 70 and older because the risk of bleeding outweighs the benefit of CV prevention. (It is recommended for people who have already had a heart attack.) Additionally, some people have salicylate allergies and it can cause Reye’s syndrome, a rare but dangerous reaction, in children and teenagers who have viral infections.

Ibuprofen (Advil, Motrin)

Positives

Like aspirin, ibuprofen is effective (probably more so) in treating common aches and pains, inflammation, and also reducing fevers. It is also less likely to cause GI irritation than aspirin. Nor is it a salicylate, so this particular allergic reaction can be ruled out. Ibuprofen has a rapid onset of relief and a short half-life. And, unlike aspirin, it does not cause Reye's syndrome.

Negatives

Ibuprofen may be "easier" but this does not make it easy on the stomach. Long-term or high-dose use can also cause ulcers and bleeding and affect kidney function (this is a common issue with most NSAIDs). And although ibuprofen is less likely to cause heart attacks it, along with all the other NSAIDs other than aspirin, do the same to varying degrees. Still, approximately 30 billion doses of ibuprofen are consumed annually in the US. Most people who use it, especially short-term, find it to be effective and safe.

Naproxen Sodium (Aleve)

Aleve and Advil are similar drugs with small but significant differences. Advil gives relief faster and Aleve lasts longer. This is why Advil is dosed 4 times daily while Aleve is given twice. The longer duration of action makes it useful for people with chronic pain. Aleve is thought to be less likely than ibuprofen to cause CV events. According to the European Society of Cardiology, it is the safest NSAID in terms of causing heart attacks.

Indomethacin (Indocin)

Positives

Indocin is a very powerful, highly effective, anti-inflammatory drug, which is used for more seriously painful conditions, such as gout, severe osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.

Negatives

Look out stomach. Indocin is arguably the worst NSAID for the stomach. Although this is difficult to quantify, Indocin earns top honors because it is typically the reference standard NSAID used in rat ulcer experiments given its propensity to cause these in the animals. The CV toxicity of Indocin is similar to other NSAIDs.

Diclofenac (Voltaren)

Positives

Diclofenac is a powerful NSAID for pain and inflammation. It also comes as a gel, which diminishes the systemic toxicity of the drug. The gel form is useful for localized pain and is much safer than the pills since the blood levels are 90-95% lower than those from the pill form.

Negatives

Diclofenac has a more complex set of side effects. While it is similar to more commonly used NSAIDs in terms of GI effects its cardiovascular profile is worse. A 2014 article in US Pharmacist concluded:

Several meta-analyses and systematic reviews indicate that diclofenac has demonstrated the highest cardiovascular risk of any of the nonselective NSAIDs

Despite having GI risks that are comparable to those of other NSAIDs, the cardiovascular concerns add another layer of caution, making diclofenac (the oral form is prescription only) much less used than ibuprofen – approximately 12 million prescriptions annually in the US vs. 30 billion doses for ibuprofen (OTC).

Celecoxib (Celebrex) - An NSAID of a different color

Positives

Celebrex, designed as a selective COX-2 inhibitor , reduces ulcer risk by around 50%. This makes it quite useful for people with chronic arthritis who may need to be taking the drug for long periods, especially those with ulcer risks. It is thought to be about as effective as ibuprofen.

Negatives

Celebrex is the only surviving COX-2 inhibitor. Vioxx and Bextra, also COX-2 drugs, were taken off the market in the early 2000s due to an unacceptable risk of cardiovascular events. At typical doses, Celebrex and ibuprofen carry about the same cardiovascular risk.

Figure 1. The chemical structures of the six most commonly used NSAIDs. Note that Aleve, Voltaren, and Indocin share a common pharmacophore, an acetic acid group bound to an aromatic ring. This is no coincidence. On the other hand, Mobic, aspirin, and Celebrex have little or no similarity to the three drugs in the left common.

Bottom line

It has been well over a century since the discovery of aspirin and heroin. One could argue that little progress has been made in treating pain. NSAIDs, although improved, and opioids remain the only classes of drugs for pain and inflammation. This remains a vital area for research (2).

NOTES:

(1) There are about one dozen approved NSAIDs but some of them are rarely used. I have focused on the most commonly used drugs.

(2) I have chosen to exclude Gilead's VX-548, an experimental pain drug that operates by a novel mechanism. It is under review by the FDA. I wrote about the drug earlier this year.

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Josh Bloom

Director of Chemical and Pharmaceutical Science

Dr. Josh Bloom, the Director of Chemical and Pharmaceutical Science, comes from the world of drug discovery, where he did research for more than 20 years. He holds a Ph.D. in chemistry.