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The Biomedical Engineering blog is the place for conversation and discussion about topics related to engineering principles of the medical field. Here, you'll find everything from discussions about emerging medical technologies to advances in medical research. The blog's owner, Chelsey H, is a graduate of Rensselaer Polytechnic Institute (RPI) with a degree in Biomedical Engineering.

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What We Don’t Know About Tylenol

Posted December 17, 2015 7:00 AM by cheme_wordsmithy

Many theories and principles in science & engineering begin with observation and experiment. We observe that something happens, develop a hypothesis about what we think is happening, and then run experiments to test our theory. Sometimes we don't have much understanding of the science and math behind our observations until after all these steps. That's the beauty of the scientific method (aaah, brings me back to 6th grade science).

This is all well and good when looking at science history (gravity… the light bulb…), but what about modern medicine? Certainly we would only use pharmaceuticals that we fully understand all the science behind… right? Well, take it as you like, but there are actually still some big unknowns surrounding one of the world's most common over-the-counter pain-reliever: acetaminophen.

Acetaminophen, better known by the brand name Tylenol®, is a drug that falls under a class of painkillers called non-opiod analgesics (let's call them NOAs). Unlike opiod analgesics (which suppress the brains perception and response to pain), NOAs (which also include ibuprofen, aspirin, naproxen, and others) work largely by suppressing the creation of prostaglandins, which cause pain and inflammation in nerves when cells are damaged. They do this by inhibiting the cyclooxygenase (COX) enzyme which helps make prostaglandins molecules. To sum up, NOAs block COX to prevent the formation of prostaglandins, thus limiting the pain you feel from an injury.

What makes acetaminophen different from other NOAs, however, is that it doesn't appear to block COX in the peripheral nervous system (nerves near the site of your injury) very much, which is why it isn't considered an anti-inflammatory like Ibuprofen (better known as Advil®). It instead blocks COX mainly in the central nervous system (the brain and the spinal cord), which is why you may choose acetaminophen more for headaches and ibuprofen more for physical injuries to redcue inflammation. However, the mechanism(s) behind how acetaminophen affects the central nervous system are still up for debate among scientists.

You can read more about the different theories that exist in this ACS article - they are fascinating. You can also check out a short video about it here. What intrigues me most, though, is how much uncertainty has surrounded such a well-used and well-accepted medicine. What does this say about our caution when it comes to the use of pharmaceuticals? Is it enough that we have billions upon billions of case studies of Tylenol® to look at? Should we be concerned about the unknowns when we think about cancers, or the known relationship between acetaminophen and liver damage?

Perhaps these are warranted reactions, perhaps they are overreactions. For me, the mystery of acetaminophen at least confirms the reality that the human body (and the biochemistry behind its workings) is incredibly complex, and there will always be more to understand and to learn.

References:

Tufts Journal

Chemical and Engineering News

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#1

Re: What We Don’t Know About Tylenol

12/17/2015 7:30 AM

The health care industry is the third leading cause of death in the US, that should be a clue that these medications are not safe, even taken as directed....

• 12,000 deaths per year due to unnecessary surgery

• 7000 deaths per year due to medication errors in hospitals

• 20,000 deaths per year due to other errors in hospitals

• 80,000 deaths per year due to infections in hospitals

• 106,000 deaths per year due to negative effects of drugs

http://www.health-care-reform.net/causedeath.htm

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#2
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Re: What We Don’t Know About Tylenol

12/17/2015 12:55 PM

Are healthy people going to the hospital? Wouldn't that tend to skew the numbers?

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#3
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Re: What We Don’t Know About Tylenol

12/17/2015 3:27 PM

These are reported by the Hospitals, you tell me.....

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#8
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Re: What We Don’t Know About Tylenol

12/18/2015 2:10 PM

Well, I guess my point is that most people who end up in hospital are already compromised in some way and that frail health could be a significant contribution to the end result.

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#9
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Re: What We Don’t Know About Tylenol

12/18/2015 4:12 PM

So if for instance, you're so sick you can't defend yourself, if someone suffocates you, they are less to blame because you are in a weakened condition?? Is that they reasoning here??

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#12
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Re: What We Don’t Know About Tylenol

12/18/2015 6:03 PM

When my Mother died about 15 years ago, It was attributed to a morphine overdose by the hospital.

She had terminal cancer and was in a lot of pain and would have lived maybe a month longer at most.

I think there are a lot of cases like that so the numbers are somewhat skewed.

My Father in law will probably die from a drug related issue. He is 91 years old and has a mechanical heart valve and needs to be on blood thinners. They are causing hemorrhaging and he is back in the hospital now and it is getting harder and harder to walk the line between not enough blood thinner and a clot forming from the mechanical valve or too much and bleeding out.

When it comes, his death will almost certainly be from either too much or not enough blood thinner, but the artificial valve has added many good years to his life.

Cases like his skew the numbers too.

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#18
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Re: What We Don’t Know About Tylenol

12/21/2015 1:52 PM

First off, I am not trying to defend the mistakes. They ARE going to happen. What we want is a systemic way to prevent them so there are far fewer of them. The point is that even a small 'error' can result in death in someone in very frail health or even the possibility that an error was committed, the patient died, but ultimately they would have died regardless of the error.

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#5
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Re: What We Don’t Know About Tylenol

12/18/2015 11:25 AM

Err, I think we could be a little more differentiated. Of those statistics the only relevant one is the 106,000 deaths per year due to negative effects of drugs. This includes all drugs, not just acetaminophen (paracetamol for the British), and the results will be skewed by the truly dangerous drugs like anticoagulants and cytotoxic drugs. Acetaminophen itself is an incredibly safe drug. Allergy is almost unknown (some 14 cases in the world literature). The associated deaths are almost always due to overdose.

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Re: What We Don’t Know About Tylenol

12/18/2015 4:17 PM

"MONDAY, Nov. 4 (HealthDay News) -- Combining acetaminophen pain relievers, which include Tylenol, and even light amounts of alcohol can more than double the risk of kidney disease, new research suggests.

Taking the recommended dose of acetaminophen, combined with a small to moderate amount of alcohol, produces a 123 percent increased risk of kidney disease, according to a new preliminary study."...

http://www.webmd.com/mental-health/addiction/news/20131104/tylenol-and-alcohol-a-bad-mix-study-suggests

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#13
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Re: What We Don’t Know About Tylenol

12/19/2015 6:17 AM

This is an interesting exercise in the evaluation of scientific evidence. The reference is to a single preliminary report, which was not peer-reviewed. No mention was made of whether the paracetamol and alcohol intakes were acute or chronic.

I would refer you to a far more useful source, being a review which not only explains how the interaction might occur, but also makes clear that the difference between acute and chronic intake is important:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014937/

In particular please note: "The position is complicated enormously because acute and chronic consumption of ethanol can have opposite effects on paracetamol hepatotoxicity."

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#15
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Re: What We Don’t Know About Tylenol

12/19/2015 4:59 PM

Sorry, but "peer-reviewed" does NOT guarantee absolute accuracy, but rather merely less chance of error.

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#16
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Re: What We Don’t Know About Tylenol

12/20/2015 3:04 AM

I will continue to refer you to the more useful source given in post #13.

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#17
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Re: What We Don’t Know About Tylenol

12/20/2015 10:55 AM

Indeed, but what are you sorry about? Do you actually prefer preliminary results because they have not been subsequently substantiated?

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#21
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Re: What We Don’t Know About Tylenol

12/21/2015 8:30 PM

I suspect there is no such thing as a safe medication. You could even choke and die drinking a glass of water.

A lot mistakes are obvious in hind site. Doctors are not perfect and don't always know exactly what's wrong with a patient. Given that they know the problem, medications do not have identical effect on everybody.

Someday we will have the knowledge to tailor drugs to a particular patients body chemistry, but the science is not there yet today. So what we have is what works most of the time with most of the patients, but there will be outliers for whom the medicines do not work well.

As for deaths due to infections in hospitals, some blame needs to be placed on the unnecessary use of antibiotics. It is surprising that this problem was not foreseen. Evolution is vastly sped up for bacteria which typically double in population in about 20 minutes. Antibiotics which kill 99.9 percent of the bacteria leave the 0.1 percent of the resistant remaining bacteria plenty of room to grow. With a 20 minute doubling time, they will fill this space in about 36 hours. We have shown our hand to the enemy, underestimating the power of genetic intelligence (evolution).

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#4

Re: What We Don’t Know About Tylenol

12/17/2015 5:40 PM

Not only are we unsure of how acetaminophen works; we found out in the past week that it doesn't work on flu symptoms. After reading Cheme's blog, though, I can extrapolate a reason why: this drug doesn't work so well outside the central nervous system. I discovered a long time ago that acetaminophen doesn't do a thing for me, but maybe that's because I usually have muscle aches and pains.

As far as using a drug whose mode of action we don't know, I present to you the case of acetylsalicylic acid. Even though the pain-relief benefits of aspirin and its original source, willow bark, have been known for millennia, its method of action wasn't discovered until 1971 (which was about the time I made some in chemistry lab in college). John Robert Vane, a British pharmacologist, shared a Nobel Prize for this discovery. Pretty important discovery!

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#22
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Re: What We Don’t Know About Tylenol

12/21/2015 9:21 PM

Another factor, not much talked about, is that the liver "learns" to metabolize foreign substances, to return the body's chemistry to normal. It is why a novice drinker gets intoxicated on a smaller amount of alcohol than someone who has consumed it for a long time.

I suspect the same is true with drugs such as Tylenol. If you take it sparingly, it's effect will be stronger because your liver has not geared up to metabolize it quickly.

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#6

Re: What We Don’t Know About Tylenol

12/18/2015 12:04 PM

Another bad, bad effect of Tylenol:

Women who have high (perhaps higher than normal) estrogen levels, and for whatever stupid reason take large doses, far in excess of labelled recommended dose, may develop a condition of the large bowel known as gluten sensitivity syndrome, gluten allergy, ciliac sprue.

My wife has it, because a moronic boyfriend years ago insists that "two is not enough, here: take eight of them". She can no longer tolerate the slightest morsel of food that contains gluten, otherwise it is a week long bout of diarrhea, lethargy, and often times symptoms of psoriasis, due to failure to absorb vitamins and other nutrients.

Thus: a strong word of caution about overdoing any over the counter medication or taking for symptoms where it might not be effective.

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#11
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Re: What We Don’t Know About Tylenol

12/18/2015 4:18 PM

I wonder if improper use of Tylenol/paracetamol has led to an increase in the number of people with gluten sensitivity. I'm sure some folks have cut gluten out of their diets not because they have symptoms (unlike your poor wife!) but because it's become something of a fad.

But there does seem to be an increased incidence of gluten-related health woes these days, and a lot of people subscribe to that same "if one is good, 8 must be better" theory the old boyfriend espoused.

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#14
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Re: What We Don’t Know About Tylenol

12/19/2015 7:08 AM

A "condition of the large bowel known as gluten sensitivity syndrome, gluten allergy, ciliac sprue" We are talking about at least two, possibly three, separate conditions here, and it is important not to lump them all together.

I know of no causal relation between high estrogen levels and bowel disease.

Finally, just because A happened before B does not mean that A is a cause of B. I understand bellyache being a cause of excessive acetominophen consumption, but know of no study showing that acetaminphen overconsumption causes bowel, as opposed to liver, disease.

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#19
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Re: What We Don’t Know About Tylenol

12/21/2015 3:14 PM

Well, trust me, the stupid physicians could not figure out what was wrong with her at all. She finally figured it out, and by the way, it is known that in women with high estrogen levels there is an effect. Over ingestion of acetaminophen combined with high estrogen levels, can and does cause cilia in the small bowel to be damaged.

When I used different terms to refer to the conditions, the main term is ciliac sprue, although, I think these are highly related conditions, in that gluten allergy is developed as a symptom in all three.

Are you a physician? Biochemist? My wife worked in the health field for many years, and has basically a super-genius level IQ. Makes you wonder why she married a fool like me, but that is entirely another matter. She had to work this out on her own with no damn help from the medical system which is effectively inept at thinking independently or scientifically. The doctors just about killed her the first time by convincing her to take poisons to "rid you of the worms and parasites" that they had no positive diagnosis for. Then it was for another round of antibiotics, followed by Flagil, because it seemed like the "right" thing to do. She quit them after that.

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#20
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Re: What We Don’t Know About Tylenol

12/21/2015 4:25 PM

Well, trust me too, there is always a patient that knows more about medicine than their stupid physicians. I can only apologise that my colleagues have not recognised the condition of ciliac sprue. All I can say in their defence is that since no anatomist has ever found cilia in the lining of the healthy or diseased bowel there is no reason to suppose that ciliary damage is the cause of any bowel disease. Indeed, cilia would find it rather difficult to function there, since the gut wall is covered by a layer of mucus. The condition is not ciliac but celiac sprue. Celiac sprue, or celiac disease, I repeat, is an autoimmune condition which has nothing to do with the enthusiastic ingestion of acetaminophen. It is not the same as gluten allergy. Moreover, gluten allergy is a disease, not a symptom.

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#23
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Re: What We Don’t Know About Tylenol

12/22/2015 1:35 PM

I apologize if I have abused the correct medical terminology, not being a physician myself, that appears to be easy enough to do.

Above is a picture I plucked off the web:

https://search.yahoo.com/yhs/search?p=diagram+of+tissues+of+the+small+bowel&ei=UTF-8&hspart=mozilla&hsimp=yhs-004

I think what I meant was that the villi sort of lay over, and become inflamed, etc., etc. My wife is certain that her condition is due to overdosing (more than once) on Tylenol. Apparently, the problems did not exist prior to the few events, and have persisted forever since.

Web MD entry:

Celiac disease -- also known as celiac sprue or gluten-sensitive enteropathy -- is a digestive and autoimmune disorder that results in damage to the lining of the small intestine when foods with gluten are eaten. Gluten is a form of protein found in some grains. The damage to the intestine makes it hard for the body to absorb nutrients, especially fat, calcium, iron, and folate.

Scanning to the end of the article, it says really nothing about the ab initio cause of this autoimmune disorder, but I think it is safe to assume it does not just appear on the horizon of its own, and that some environmental factor(s) trigger the onset. I think Tylenol in large overdose with high estrogen is apparently one of the triggers, and if you don't believe me, then you suck.

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#24
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Re: What We Don’t Know About Tylenol

12/23/2015 4:44 AM

In other words: "my mind is made up. Please don't confuse me with the facts". If your wife chooses to be the only person in the universe who develops celiac disease as a result of Tylenol then I await her pronouncements on rocket science with interest.

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#25
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Re: What We Don’t Know About Tylenol

12/23/2015 8:16 AM

Not so fast..

She is not the only person in the universe that has had this issue. It is not from "taking" Tylenol, but from ingesting over 4 times the recommended dose, and doing that repeatedly.

As far as post #23 goes, I do not particularly like the wording in that blurb from WEBMD, as they seem to imply that gluten containing products cause the disease. In fact, nothing could be further from the truth. Gluten does not cause the syndrome in the first place, or else it would have been evidenced even as early as childhood? I don't know for sure, but I would be willing to wager that some other environmental factor as Tylenol (in excessive doses), TNT exposure, ingestion of radioactive isotopes such as Strontium 90, or many others could damage the lining of the small bowel. The gluten is just the particular fuel that "lights up" the condition, resulting in an allergic inflammation reaction.

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#26
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Re: What We Don’t Know About Tylenol

12/23/2015 8:42 AM

And by the way, from what she related to me, the amount of Tylenol she took should have "cooked" her liver. Apparently, that is not her problem at all, strange bird that she is.

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#27
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Re: What We Don’t Know About Tylenol

12/23/2015 8:50 AM

I refer you again to the first sentence of post #24.

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#28
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Re: What We Don’t Know About Tylenol

12/23/2015 9:57 AM

I am going to settle this argument once and for all: (1) I must now retract everything I said about Tylenol, as this medicine was not the culprit at all. I went back to my wife and asked her once more, and she straightened me out: she can take Tylenol, what she cannot take and what "did her in" was large doses of NSAID drugs such as aspirin or ibuprofen, totally not the same thing. (2) I apologize for being an obstinate anal orifice about this. I like Tylenol, and take it every time I have a sinus or tension headache (not that often). Link to:

http://www.webmd.com/ibd-crohns-disease/news/20000907/most-pain-relievers-unsafe-for-inflammatory-bowel-disease

"Researchers from New York City's Lenox Hill Hospital found that patients with inflammatory bowel disease should avoid not only ibuprofen preparations like Motrin, Advil, and Nuprin, but most other anti-inflammatory pain relievers as well, including Ecotrin and all medications containing aspirin." - Not the precise study I was searching for, and am having difficulty finding it, but further down in the article it says this:

"The study, published in the August issue of The AmericanJournal of Gastroenterology, suggests that patients with inflammatory bowel disease should avoid medications belonging to the class known as nonsteroidal anti-inflammatory drugs (NSAIDs), because they both aggravate symptoms of the existing disease and may actually cause disease onset in people who are predisposed to the condition." - a little bit more on target here.

Now this link sort of "blows me away"! - possible link between Tylenol and leaky gut syndrome (also mimics or is correlated with gluten allergy).

http://www.allergy-details.com/gluten-allergy-c/gluten-allergy-and-ibuprofen/

See Wheat, Gluten and Asthma for more information on this.

Leaky gut syndrome is a condition where larger molecules and even partially digested food and bacteria finds it's way into your bloodstream. This causes all kinds of leaky gut symptoms, and can cause allergies, such as gluten allergy.

Ibubrofen over-use is known to deplete folic acid. According to the School of Medicine and Health Sciences, folic acid deficiency "harms DNA metabolism, thus causing abnormal cellular development, especially in cells that have a higher rate of turnover. These include red blood cells, leukocytes, epithelial cells of the stomach, intestines, vagina, and uterine cervix".

According to some sources, it is possible that ibuprofen affects the gut of some people more than others. People with Crohn's disease and their relatives seem more likely to develop leaky gut when they take ibuprofen. This suggests that the same will happen for anyone who takes too much ibuprofen.

Yet, my wife seems to think she is OK with normal or limited doses of Tylenol. Her condition is very confusing, hard to tell what food will set it off, and we go to great length to read labels of food, looking for such things as "modified food starch", wheat, oats, etc. Mostly, she is better off with foods that are simple, unprocessed items. I think I do need to get her to start taking Folic acid to help repair cells, etc. I think there is something in common with leaky gut, because sometimes she complains of difficulties with breathing, and dust removal helps, air filtration system helps, UV treatment of duct air helps, but also her breathing issues go away quite quickly. Her condition is really taking a heavy toll of her quality of life, as she virtually never leaves the house now.

http://www.healthnowmedical.com/blog/gluten-intolerant-this-dangerous-drug-creates-a-leaky-gut

This is probably the link that really ties in NSAID with leaky gut the best, and mentions at least a doctor of medicine that has researched this. It mentions NSAID being responsible for turning on the celiac autoimmune gene.

In summary, I do apologize, that all I did previously was muddy the water. I hereby denounce my previous statements, and if I inferred you to be a body part located near the buttocks, I fully apologize.

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#29
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Re: What We Don’t Know About Tylenol

12/24/2015 3:56 AM

You're welcome. Happy Christmas.

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#7

Re: What We Don’t Know About Tylenol

12/18/2015 12:55 PM

Just about EVERYTHING we ingest is a POISON to some degree or another, making 'informed' moderation the KEY to staying alive.

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