This was an extremely difficult post to write. I live in war-ravaged Portland, Oregon, and it is like World War II here. Think Berlin at the end. Nothing but chaos, death and destruction. A burning hell hole. I sit in my cellar, the walls shaking from the brown bombs and artillery. Using the light from the burning house next door to see the text. I will upload this to Starlink using an old 300 baud modem, powered by the fading battery of an abandoned Cybertruck. Thank you, Mr. Musk. At least we will soon have National Guardsmen in the city who will certainly be able to stem the Red tide. But if I don’t survive this hellscape, remember, Keep Portland Weird.
I was never much of a fan of acetaminophen, either personally or professionally. As a clinician I was rarely responsible for pain control of patients. And I have long been of the learned opinion that, with a few exceptions, treating fever is either a waste of time or counterproductive.
My early clinical experience with acetaminophen was as a resident with Tylenol overdoses. I took care of one or two a year, and since it was slow, it was a particularly awful way to die. The pattern was consistent: someone would swallow a bottle of acetaminophen as a gesture. Nothing would happen, and a day or so later would show up in the ER, chagrined and embarrassed but wanting to make sure they were OK. They were not. Acetaminophen had killed their liver and they would go on to die of liver failure, usually over the course of a week and regretting it to the end. Did not make me a Tylenol fan.
Personally, I never found acetaminophen did anything for pain, especially compared to NSAIDs. It did not even have a placebo effect that I could tell. A great big nothing burger.
It is a drug that is so ubiquitous that I cannot ever remember either being taught about it in medical school or elsewhere. Acetaminophen is. It requires no further explanation.
Then my total knee replacement, a most unpleasant experience. Not really painful, I needed no narcotics after 48 hours, just uncomfortable and limiting. But I was told to take Tylenol around the clock, as it would make me more comfortable and would potentate the oxycontin should I need some. So I did, despite my opinion that acetaminophen is worthless. I try and do what I am told, since my medical knowledge outside of ID is sketchy at best. The doctor who treats themselves has a fool for a patient and an idiot for a physician.
But I wondered. How efficacious is acetaminophen for pain? What kinds of side effects outside of killing the liver and kidney could I expect?
Pain
Searching PubMed with acetaminophen and pain results in 10,805 hits. Slightly more than I want to read. So this screed will, by necessity, be targeted.
I was curious how acetaminophen was found to be a pain killer. Pain wounder. Pain annoyer. It appears that acetanilide is an old analgesic. Investigations into its metabolism in the 1940s revealed that acetanilide is metabolized to acetaminophen, the sort of kind of perhaps maybe active molecule.
I guess they assumed that, since acetanilide was an analgesic, so was acetaminophen. But when I look for anything that resembles proof of analgesia, for acetanilide, I cannot find much. There is a series of cases from 1889 that concluded
Allowing for the fallacies in estimating therapeutic effects where reliance has almost solely to be placed on the statements of patients, these results are satisfactory, and justify the hope that exalgene may take a useful and important place among the remedies by which pain is relieved. Its analgesic power is not a very powerful one, but it has the enormous advantages of being free from the disturbance and inconveniences that are associated with the action of nearly all other pain-subduing agents and for the dangers inseparable from the use of the more powerful of these agents.
The more things stay the same, the more things stay the same. And I love the style of these old medical journals.
Acetanilide was also used as an antipyretic for diseases like typhoid fever back in the day, and fevers can be uncomfortable with myalgias and headache. I wonder if the supposed analgesic effect of acetanilide was more a side effect of fever relief.
But it was assumed for a long time that acetaminophen was an analgesic based on little to no clinical data.
In 1948 there was a study, the details I cannot get, that showed acetaminophen increases pain threshold to thermal injury. Acetaminophen use for pain started in 1950, but the first clinical trial of acetaminophen monotherapy (the 50s and 60s were big on polypharmacy) I could find was in 1967.
I came across this title from 1965: On treatment of the “pain” symptom in obstetric and gynecologic pathology. I like that pain was in quotes. Oh, those hysterical females and their “pain.”
But if you wander the Pubmeds, the conclusion you will come to is that acetaminophen is the worst of all the analgesics, depending on the pain treated. Barely better than or equal to placebo.
One nice summary from 2016 suggests
- Paracetamol at doses between 500 and 1000 mg is in the least effective quartile of drugs for treating acute postoperative pain.
- Paracetamol 1000 mg has modest efficacy in migraine and tension-type headache.
- Paracetamol at doses up to 4000 mg daily is ineffective in back pain.
- Paracetamol at doses up to 4000 mg daily is practically ineffective in arthritis. Though marginally better than placebo, paracetamol has little chance of achieving clinically meaningful benefit in osteoarthritis.
- No review evidence that paracetamol works for dysmenorrhoea, neck pain, rheumatoid arthritis or cancer pain.
Migraine seems the best use. Which is odd. There are many types of pain, so why would acetaminophen be most efficacious against migraine?
I found two studies (one, two) using oral acetaminophen alone vs. placebo and both studies demonstrated efficacy. One even showing acetaminophen was “highly effective.” But both studies were run by the makers of Tylenol. Now that does not automatically invalidate the study, but pharma-funded studies often have better results than independently funded studies.
Studies sponsored by pharmaceutical companies were more likely to have outcomes favoring the sponsor than were studies with other sponsors (odds ratio 4.05; 95% confidence interval 2.98 to 5.51; 18 comparisons).
My rule of thumb, pulled out of thin air, was to whack 30% off the results of all pharma sponsored studies. So “highly effective”? Meh. I see a bit of hype.
IV acetaminophen, which should act faster, but
The results indicate, that 1000 mg intravenous acetaminophen is not superior to placebo in treating severe acute migraine attacks.
This study was paid for by an unrestricted grant from Bristol Meyers Squibb, the makers of IV acetaminophen but run by university hospitals. So I lean towards the idea that acetaminophen is likely overrated for migraine treatment.
As an aside, it looks like Bristol Meyers Squibb, makers of Excedrin, and McNeil, makers of Tylenol, have battled over which product is superior.. Whose OTC pain reliever will reign supreme? Not Tylenol.
I was curious about its efficacy for total knee replacement pain. Pain, at least from my experience, is not experienced as a single entity. Acute or chronic, all the pain I have had hurts in different ways. With the knee replacement I have at least 4 different and qualitatively distinct pains. But the team was adamant that I take Tylenol round the clock and I try and do what I am told.
So the data?
All over the map, but unimpressive. For example, one meta found
Our meta-analysis results indicated that compared with a control group, intravenous acetaminophen was associated with reductions in total morphine consumption and visual analogue scale (VAS) score at postoperative day (POD) 3. However, there was no significant difference in morphine consumption at POD 1 or in VAS at POD 1 or POD 2. Moreover, there was no significant difference in the length of hospital stay.
Not the kind of pain relief I would have found impressive, although I would note that the length of stay in these studies was 3 days. So also not applicable to my knee replacement, as I spent the night and was discharged by noon the next day, less than 24 hours from the end of my surgery. And I needed no oxycontin for pain after 36 hours, so also not applicable; at least to me.
And another found decreased narcotic use all three days post-op:
Additional intravenous acetaminophen to multimodal analgesia could significantly reduce pain and opioid consumption after total joint arthroplasty with fewer adverse effects.
But a more recent double-blind study found
acetaminophen to preoperative preemptive multimodal analgesia did not decrease postoperative morphine use or ameliorate pain relief.
Which is consistent with the overall literature on acetaminophen and pain: it does little to nothing.
Side Effects
48 hours post-op, I was only taking the Tylenol. And I noticed that I felt like crap an hour after the dose: headache, slight nausea, sweating and a general malaise that faded until the next scheduled dose. It turns out these symptoms are common with acetaminophen, so I stopped it. The symptoms resolved and there was zero change in the various pains in my knee. The acetaminophen was doing squat.
I do not mention my experience with acetaminophen as any sort of proof. The plural of anecdote is still anecdotes, not data. And the pleural of infection is empyema. I do so to note that my experience is consistent with the literature: acetaminophen is next to worthless as a pain reliever. It is no better than acupuncture for pain relief. Its role in pain control would be like that of acupuncture: when there is nothing to offer that is effective, at least you pretend to do something to treat the pain. Which brings us to pregnancy.
Pregnancy
You have a pregnant person with mild to moderate pain. Headache. Sprain. Migraine. Well, migraine is not so mild to moderate. What are you going to offer? Not a lot of options. So it’s acetaminophen. Which is as close to doing nothing as doing something will allow. Because patients are not fond of being told there is nothing to do, it will get better on its own. So acetaminophen it is. Safe and unlikely to be effective but with the added benefit of multiple side effects.
Kind of an odd place to be: yes, based on the medical literature, I can defend this drug as safe for your fetus, but for you it offers little to no efficacy and a fair number of toxicities. I might as well suggest acupuncture. Same operative characteristics for pain and I can find no reports of acupuncture harming the fetus. Why would it, outside of an amazing poorly placed needle?
I suppose you could try and educate the patient, but I suspect that will go nowhere. I think the literature is clear that, with a few exceptions, treating a fever at best does nothing to alter the course of infection and, at worst, leads to more prolonged disease and complications. Fever relief only makes the patient more comfortable. I have been saying don’t treat fevers for decades and made zero impact whatsoever on the treatment of fevers. Hell, when my kids were febrile, my wife gave them Tylenol, completely ignoring me.
Like treating a fever, I would wager using Tylenol for pain is too ingrained in society to be amenable to change. Unless you want to use fear based on fictions to alter behavior, and I am not a fan of lies as a motivation technique. A pity, as
Besides, as the vilest Writer has his Readers, so the greatest Liar has his Believers; and it often happens, that if a Lie be believ’d only for an Hour, it has done its Work, and there is no further occasion for it. Falsehood flies, and the Truth comes limping after it; so that when Men come to be undeceiv’d, it is too late; the Jest is over, and the Tale has had its Effect…
So acetaminophen will continue to be the most commonly used ineffective drug for pain.
