> (But, yeah, naproxen seems to be one of the safest ones...)

Kind of.

But it starts to feel a little uneasy taking it all the time once you realize that naproxen's regulatory approval came from https://en.wikipedia.org/wiki/Industrial_Bio-Test_Laboratori... data.

All stomach effects are due to decreased prostaglandin levels. All NSAIDs function through inhibition of prostaglandin synthesis.

The exception is Tylenol/acetaminophen, as it doesn’t have an anti-inflammatory effect / doesn’t seem to act primarily on COX1/2. It’s currently popular to bandy about the theory that it targets spinal COX3.

https://en.wikipedia.org/wiki/Nonsteroidal_anti-inflammatory...: "NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protective prostaglandins" (emphasis added)

Aspirin and many other nonsteroidal anti-inflammatory drugs (NSAIDs), (eg, ibuprofen, naproxen, indomethacin, and ketorolac) are carboxylic acids. Their pKa values range from 3.50 (aspirin) to 4.85 (ibuprofen). As such, they are not ionized at the acidic pH found in the gastric lumen and thus can be absorbed across the gastric mucosa. Once these drugs move from the acidic environment of the gastric lumen into the pH–neutral mucosa, the drugs ionize and are trapped temporarily in epithelial cells where it may damage these cells. How important is this effect? Calcium carbsalasate does not have this epithelium damaging topical effect, but causes the same ulcerative outcome[1].

This "topical" epithelial injury by many NSAIDs does not appear to be of prime importance in the pathogenesis of clinically important endpoints (symptomatic ulcers). The pathogenesis of symptomatic peptic ulcer disease caused by repeated exposure to NSAIDs is mainly a consequence of systemic (post-absorptive) inhibition of gastrointestinal mucosal cyclo-oxygenase (COX) activity. Even intravenous or intramuscular administration of aspirin or NSAIDs can cause gastric or duodenal ulcers in animals and humans [2].

PMIDs: 1 - 18242146 (“The incidence rate of peptic ulcer disease is similar in patients using low-dose effervescent calcium carbasalate compared with regular low-dose acetylsalicylic acid. This implicates that peptic ulcers seem to be related to systemic rather than to local effects of low-dose acetylsalicylic acid.”) 2 - 631484 (“These studies show that when the stomach is acidified by giving histamine intravenously or HCl intragastrically, intravenous aspirin produces large deep gastric ulcers.”)

The above is a partial paraphrase from UpToDate.

That study also raised concerns about older NSAIDs (including aspirin, acetaminophen and ibuprofen):

http://circ.ahajournals.org/content/115/12/1634