Acetaminophen Is Safe for Your Stomach, Right? Maybe Not!

Ask almost any health professional about pain relievers and you will be told that NSAIDs (nonsteroidal anti-inflammatory drugs) can be hard on the digestive tract. That includes medications like aspirin, celecoxib, diclofenac, ibuprofen, indomethacin, meloxicam, naproxen and piroxicam. Such drugs can cause heartburn and ulcers. In some cases, those ulcers can bleed or eventually eat a hole through the stomach lining (perforated ulcers). But people in pain need relief! So, if an NSAID is causing GI problems, most physicians, nurse practitioners, physician associates and pharmacists will say that acetaminophen is safe and a great alternative.

Brand name Tylenol and generic acetaminophen products are supposed to be gentle on the GI tract. A study in the journal Arthritis Care & Research (November 24, 2024) suggests, however, that older people may be more vulnerable to acetaminophen toxicity than previously imagined.

Acetaminophen and PUB (Perforation or Ulceration or Bleeding):

The authors introduce their study this way:

“Almost all clinical guidelines advocate acetaminophen as the first-line oral pharmacological treatment for pain due to osteoarthritis (OA), mainly because of its perceived safety over other oral analgesics. However, recent studies have raised concerns that acetaminophen may be not as safe as previously thought.”

These researchers were asking a fundamental question:

Is Acetaminophen Safe for Older People?

Here is how they describe their findings (PUB stands for “perforation or ulceration or bleeding):

“In this large study of 180,483 acetaminophen exposed participants and 402,478 unexposed participants aged 65 years and older in the UK primary care population, we found that acetaminophen exposure was associated with an increased incidence of PUB, uncomplicated peptic ulcers, lower GI bleed, heart failure, hypertension, and chronic renal failure. A dose-response relationship was observed for PUB, uncomplicated peptic ulcers, and chronic renal failure.”

They add:

“The findings of our study are consistent with previous observational studies that have reported an association between acetaminophen intake and the risk of GI complications and hypertension.”

Wait…Most Health Professionals Believe Acetaminophen Is SAFE!

How could it be that the guidelines and the vast majority of health professionals believe that acetaminophen is super safe for all ages while this study says not so fast? The investigators acknowledge that their research is “observational” in nature.

And they readily admit that:

“The majority of acetaminophen RCTs [randomized controlled trials] have not found any major adverse effects…”

They answer that seeming paradox this way:

“This is because the RCTs were primarily designed for efficacy rather than adverse events, solely reported short-term effects, were less powered, and recruited healthier and younger participants.”

In other words, if everyone assumes acetaminophen is safe, if the randomized controlled trials are fairly short in duration and many of the subjects in the studies are relatively young and healthy, you might not see long-term complications, especially in older people.

In this study, the relative risk for perforation or ulceration with acetaminophen was 24% and the risk for “uncomplicated peptic ulcers” was 20%. GI bleeding lower in the intestinal tract was reported as a relative risk of 36%. That is pretty scary since that sort of complication can be tricky to diagnose.

The authors conclude:

“Despite its perceived safety, acetaminophen is associated with several serious complications. Given its minimal analgesic effectiveness, acetaminophen as the first-line oral analgesic option for long-term conditions in older people requires careful reconsideration.”

Questioning the Idea That Acetaminophen is Safe:

I know that most health professionals believe that acetaminophen is safe…full stop! End of discussion. This observational study will come as a shock to them and to patients. There will no doubt be push-back from the pharmaceutical industry, guideline committees that insist acetaminophen is safe and the majority of health practitioners.

The authors offer a mechanistic explanation that we won’t describe here. Anyone who wants to read the article can find the full-text version at this link. If you take the time to read it, you will discover numerous references to other research that supports these findings.

The results of this research do not shock me. That’s because the authors of the study point out that:

“Acetaminophen is a major metabolite of phenacetin, which has been associated with hepatotoxicity and renal damage, but the mechanism of renal toxicity due to acetaminophen is still debatable.”

When I was writing the first edition of The People’s Pharmacy (St. Martin’s Press, 1976) I discovered:

“Phenacetin, a pain-reliever much like aspirin (though somewhat less effective), has the potential to cause kidney damage if consumed frequently and in large doses. Frequently means more than ten days straight, and too much would be considered more than six tablets per day. Products which contain phenacetin include A.P.C, A.S.A. Compound, Bromo-Seltzer, Coryban-D, Empirin Compound, and Sinustat. Too much of any of these pills could promote serious kidney trouble.”

Later in the book I go on to mention that:

“Consumers Union’s medical experts have advised that people should stay away from pain-relievers that contain this drug. Since June, 1973, Canada has banned the sale of all preparations that have phenacetin coupled with aspirin.”

Phenacetin was first developed in 1878. It became quite popular in a combination product called A.P.C.:

• Aspirin
• Phenacetin
• Caffeine

Empirin Compound was one of the best known and most successful combination analgesic brands. When the handwriting was on the wall that phenacetin was potentially toxic to the kidneys, I spoke with the leadership team behind Empirin Compound.

These very high-level researchers at Burroughs Wellcome told me that Empirin Compound would no longer contain phenacetin. When I asked if they would substitute acetaminophen for phenacetin, I got an interesting reaction from these key individuals. The answer was an unequivocal no! Empirin would just contain aspirin.

Phenacetin was pulled from the American market in 1983. The reason was kidney damage. There were also concerns about cancer.

The active pain-relieving metabolite of phenacetin is acetaminophen. I am not saying that acetaminophen is dangerous or that it should be stopped. All I am doing is reporting on the most recent epidemiological research published in the journal Arthritis Care & Research (November 24, 2024).

Final Words:

I am dismayed that pharmacological researchers have been unable to develop a highly effective and very safe analgesic to deal with pain. Every over-the-counter oral pain reliever on the market has the potential to cause some people some trouble. I worry less about short-term treatment, though. Someone with a headache or a sore shoulder is not likely to get into much trouble with acetaminophen or ibuprofen or naproxen. Acetaminophen is safe for short-term use.

Where I get concerned, however, is long-term use, especially in older people. These folks have a number of painful ailments, like osteoarthritis. The temptation to use a pain reliever multiple times a day for years, or even decades, is quite strong. And I get it. When your joints ache, you want relief. I just hope that older people are not getting that relief at the expense of their digestive tracts or kidneys.

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