Have Pain? Pick Your Poison

By Josh Bloom — Oct 25, 2016
It's reflexive. Got a headache? Scarf down some Tylenol, right? But when that doesn't work, why not try Cap'n Crunch. That's because Tylenol, the weakest painkiller out there, may be even more useless than many people already know. And also more harmful. 

If you haven't read "Gonna Throw Away Your Used Narcotics?" you might want to take a look. It's about stupid government. OK, that doesn't narrow it down much. It's really about how we have gone from 60 to zero in 2.5 seconds (1) in our policies about the use of narcotics—even for legitimate, essential purposes—and the two terrible choices that we are left with: non-steroidal antiinflammatory drugs (NSAIDs) and acetaminophen (Tylenol). 

A new study suggests that we may have to recalibrate: One terrible choice, and one really terrible choice, because Tylenol, the weakest painkiller out there, may be even more useless than many people already know. And also more harmful. 

Andrew Moore, an Honorary Senior Research Fellow at the University of Oxford, certainly gets it. His new piece on The Conversation's website may make you wonder why each year in the US about 25 billion doses of the stuff are sold.

"Paracetamol (2) has been around for over 50 years. It’s safe and many guidelines recommend it as the go-to treatment. At least, that’s the conventional view of the drug. It’s a view so ingrained that it’s rarely questioned. The trouble is that the conventional view is probably wrong."

The "conventional view" that Moore writes about is that Tylenol, which is a

"stomach-sparing" painkiller, does indeed spare your stomach (3). So does Cap'n Crunch. And neither of them has any use in controlling back pain, or arthritis, according to a systematic Cochrane review. It does not mince words (emphasis mine): "We found that paracetamol does not produce better outcomes than placebo for people with acute LBP [lower back pain], and it is uncertain if it has any effect on chronic LBP."

If this bit of information gives you a headache, you're out of luck. The same review concluded that only one in ten people with headaches will derive any benefit from the acetaminophen. For post-operative pain, it's one in four, which prompts Moore to write: "These [the data from the reviews] are robust and trustworthy results. If paracetamol works for you, that’s great. But for most, it won’t."

Maybe it doesn't work, but at least it's safe. Except when it isn't.

Tylenol's reputation as a benign drug is not deserved. It is not especially safe. Acetaminophen has a low therapeutic index (TI), which means that the difference between an effective dose and a toxic dose is small (4). So small, in fact, that in 2011, the maximum daily dose of acetaminophen was reduced from four grams to three, and the amount allowed in narcotics such as Vicodin and Percocet was reduced to 325 mg per pill (3). 

There was exactly one reason for this change—liver toxicity. Although acetaminophen itself is not toxic to the liver, the liver unintentionally poisons itself (5). The drug is oxidized in the liver to N-acetyl-p-benzoquinone imine (NAPQI), a metabolite that is 50 shades of nasty. Under normal circumstance, the stuff is rapidly neutralized by ubiquitous glutathione, however, when too much is present, this process is overwhelmed, allowing the NAPQI to build up and cause permanent liver damage. 

The reason that Tylenol is not benign is the size of dose that it takes to make it "work," and how close this is to a toxic dose. The minimum dose that causes toxicity in adults is 7.5-10 grams per day and the median lethal dose (from liver failure) is 24 grams. Prior to 2011, when four grams was the maximum daily dose, it is evident that the TI was about two (7.5/4.0), which dwells somewhere between "terrible" and "hideous" on the spectrum of pharmaceutical atrociousness . Even at three grams, the TI is three, which is slightly less terrible. By comparison, the TI of Valium, which is so restricted that you pretty much need to hold up a drug store at gunpoint to get any, is 100. Yes, when comparing acute doses, Valium is 50-times safer than Tylenol. Bet you didn't know that.

Ironically, when people overdose or attempt suicide by taking a large dose of Vicodin or Percocet, it is not necessarily the narcotic that does the damage, which is made rather clear in a 2013 article in Pro Publica: "If a person dies after taking Vicodin, the FDA report does not say whether it was caused by hydrocodone or acetaminophen..."

So, what are you supposed to do when you get old and things hurt (7)?

Coming up next: Your other bad choice—Advil and its NSAID buddies.


(1) The Porsche 918 Spyder, which can be had for a mere $845,000, is considered to be the fastest accelerating car in the world. It goes from 0-60 in an incredible 2.5 seconds.

(2) Paracetamol is just another name for acetaminophen. It is used more frequently in other countries, especially Britain.

(3) But not entirely. An observational study  in Annals of the Rheumatic Diseases showed (maybe—the study is a bit weak) that Tylenol does cause stomach bleeding, just not as much as aspirin or ibuprofen.

(4) Other terms that are synonymous with therapeutic index include safety window and therapeutic window.

(5) Before 2011 Vicodin and Percocet were sold with different doses of both the narcotic and acetaminophen. If the bottle said 7.5/750, that meant that the pill contained 7.5 grams of the narcotic and 750 mg of acetaminophen. Now, the doses are 7.5/325, 5/325, etc.

(6) This assumes that livers have the wherewithal to make poor decisions. This is open for debate.

(7) Little known fact: The Cap'n was promoted and is now Admiral Crunch. Or is it Ad'mril Crunch?

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.

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