Ep 120 Acetaminophen/Paracetamol: Pain. Killer.

to point out a travel sized bottle of mouthwash. She loved how it fit in her hand so easily. That's when her dad picked up the bottle of extra strength Tylanol. They headed home together. She didn't know then it would be the last time.

sounds like erin. You'll call it paracenamol, And both are entirely correct in pretty much every single paper I read, acetaminifin is cited as the most popular and widely used over the counter medication, possibly of any class, but certainly of analgesic anti pyretic medications, that is, pain relievers and fever reducers. And this is like worldwide, worldwide. Is true, it's a very common medication on its own, but it's

also very common in combination medications. Like all of those coffin cold mixes that you buy, almost all of those have acetaminifin in them. Some studies suggest that nearly eighty percent of for example, the US general population use acetaminifin at some point in their lives, if not on the regular. And because of this, acetaminifin is also in many countries the most commonly used drug in intentional overdoses, as well as responsible for the most unintentional medication over in a

lot of countries. And we'll talk about why that's so important in terms of the dangers of acetamenifin. But first, like what does it actually do? Like what what does the ceeda menafin do? What is it? What does it do to you? No one knows, That's what's the answer, as always on this podcast. So like I mentioned, it's bought and sold as an antipyretic meaning a fever lowering and an analgesic meaning pain reducing medication. So it reduces

pain and it reduces our fever. And like you said, as it turns out, we don't fully know how it actually does this, and that fact alone still blows my mind. Like I knew that we didn't fully know the mechanisms of acetamenifin, but it was astounding to read so many papers about the potential theoretical mechanisms of this drug and have them all be like, so, just what we hypothesize on other people hypothesize this so well, who knows?

be used as an antipyritic reduces temperature. In that episode, which was all the way back in season two, yeah right, yeah wow, I talked in detail about inflammation, the process of inflammation, the indicators of inflammation like redness, swelling, pain, and heat. And I talked in more detail than I realized about one of the main pathways that mediates inflammation, and this is something called the arachotonic acid pathway. I promise it's not going to be too heavy biochemistry in

this episode, so please don't tune out. But I talked specifically about these enzymes called cyclooxygenase or cox enzymes, so to review that, because none of us remember, a racktonic acid is this substance that's present in all our cells. It's in our cell membranes and it is released when we have damage to our cells and then metabolized by cox enzymes into a whole bunch of different molecules like

prostaglandins and leukotrienes and thromboxanes. These are different kinds of signaling molecules that induce inflammation, which again you'll have swelling and pain and heat things like that. Right when we have inflammation. En sids like aspirin and ibiprofen are what are called cocks blockers. But and in blocking these cox enzymes, they act as anti inflammatory medicines, and that is how

they reduce pain and swelling and temperature. But pain is not just from inflammation, and neither is fever or rather our temperature regulation. Pain is incredibly complex and probably worthy of its entire own episode someday if we can figure out.

signals are scent without any actual damage. And then we can also have mixed pain, like pain that comes from a lot of different sources. And our temperature regulation process is mostly mediated in our brain, but there are a lot of messengers and receptors that are involved in this process. So back to what we're actually talking about. Acetaminifin is not an end set. It's not like aspirin, like a coxblocker. It doesn't work directly by this Cox pathway, but it

kind of works by that pathway. And the reason that I brought it all up is because we thought for a really long time that that is the way that it worked. So there is still confusion out there as to what the effects of thailanol are on inflammation. But as it turns out, thilanol doesn't affect our inflammatory pathways at all, and yet it still mediates both pain and fever, but by a different mechanism than things like iboprofen and aspirin, which is really cool.

that pain is kind of mediated. Besides inflammation, there are three main pathways by which acetaminifin probably we think exerts its effects, and one of them does in fact involve COX cyclooxygenase. So it was worth me telling you that whole story. So it turns out that we thought for a long time a cetaminifin worked very similarly to iberprofen just blocked this enzyme. It turns out, does do some COX blocking, but it's neither direct nor is it universal

in our body. So rather than binding to this enzyme and blocking its activity, it seems more likely that aceenamtiphin what it does is reduce the active form of this enzyme, not like reduce the amount of it, but like oxidation reduction. Reaction donates some electrons and renders it inactive in that way. But and here's where it gets really fun and interesting. Acetamnafin seems to only do this in our central nervous system, not in all the cells in our body like most COX inhibitors.

fenolamine huh, AM four O four it's easier. This molecule happens to be a weak but present agonist of our cannabinoid receptors in our brain, So this ends up leading to an increase in cannabinoids and has an effect on this other receptor that's related. Okay, what does that actually mean, I'm lost? Yeah, cannabinoids. Does that word sound familiar?

our temperature regulation. Turns out that this molecule that acetamenifin can turn into in our brain AM four four acts on these receptors indirectly and increases the production of cannabinoids that interact with these systems and then mediates both pain and temperature in our brain. Through these receptors.

our descending inhibitory SARAH to nergic pathway. So many words, so much complication, but okay, let me simplify. When we have an injury or tissue damage or whatever, and pain is a result, that information of pain is transmitted from our skin or wherever that injury is through our spinal cord and through what's called the dorsal horn of our spinal cord and then up to our brain via these ascending pathways. Right, like skin, spinal cord brain, the pathway

goes up. Then our brain has these other pathways that go back down through our spinal cord and then out to the periphery. These are called descending pathways. One of these descending pathways involves serotonin, which most people have probably heard of because of things like serotonin reuptake inhibitors or antidepressant medications. Serotonin is like a happy hormone, right. Serotonin via this pathway helps to mediate decrease the perception of pain. Right.

So it's like our brain gets a signal, ah, we have pain, and it has these pathways to go. It's cool, man, we can deal with it. We don't have to feel the hurt. That's this very simplified way of looking at it. But by activating these inhibitory pathways, these serotonin pathways, acetamenafin likely has at least some small effect on the sensation of pain via these serotin pathways as well.

that pain is coming from. And it's likely these multiple little mechanisms that all together produce the overall effect.

that's been shown in some studies. Things like rheumatoid conditions and things are not very well treated with something like acetaminifin. In some things like osteoarthritis, which is more of a direct pain rather than an inflammatory pain. Some studies have shown it's about equivalent or maybe a little less effective than something like n sets for that kind of purpose. So in general, it's considered pretty similar in terms of

pain reduction to something like an ibiprofen. Okay, some studies show that it does fairly well at things like cancer pain, at least mild cancer pain, not severe cancer pain. And migraine headaches, though I feel like a lot of people with migraines would disagree with that, and is less good for things like tension headaches. So it's like very specific types of pain that it seems to be more effective versus less effective.

treat mild pain mild fevers. The difference often is cited as the risk of these two medicines, and depending on what paper you read and who you talk to, you might think that one is very risky and the other is not. But which one might be up in the air for a long time By a lot of people. Acetaminifin was considered very, very, very safe and safer compared

to n sets. The reason for this is because n sets do have a significantly increased risk of GI side effects, specifically bleeding from the gastrointestinal tract, and that is because of their effects on cocks peripherally and in our stomach. That's a whole episode on its own, but it greatly does increase the risk of gastrointestinal bleeding more so than a seedaminifin. However, that's not to say that a cetaminifin

is without risk. And so I think in recent years, as we've learned more and more about acetaminophin, the risk benefit calculus for some people and in some of the studies that I read, has perhaps shifted. And so especially if you're talking about short term versus long term use and degree of severity of the possible side effects, one could argue that a setaminifin might be more dangerous than hyberprofen and some people do argue that in the literature.

So let's talk about the adverse effects of acetaminifin.

toxicity occur? If this medicine is super safe, and if all of the effects that I talked about with a ceedaminifin are in the brain, why is the liver involved all of a sudden, Well, our liver metabolizes acetaminafin unsurprising, our liver does that for most things, and the majority of a cedaminifin is metabolized in a way that produces the various substances that we talked about that cross into our blood brain barrier and exert their effects and help

us feel better. Right, most of the way that our liver metabolizes a seedaminifin is all great, but our liver is complicated, and it actually has multiple pathways by which it metabolizes a seedaminifin. It's not just one and one of these pathways, which most papers I read say, accounts for about five to fifteen percent of the total metabolism of acetamenifin, uses one of our systems in our liver called the cytochrome P four fifty system, and this results

in an incredibly toxic metabolite called nap qi. I'm not going to try and say the real name. And it turns out that this specific metabolite is really toxic to our liver cells. So when that is produced, it can then just kill off the liver cells right around where it's produced. Now, most of the time, we have enough of another molecule hanging out in our liver called glutathione that neutralizes this toxic metabolite, So no problem, we make a little bit of it, but we can neutralize it.

But if this metabolite is produced in excess, say from too much a sedaminifin that we take too much at one time, we run out of this gluteithione, so then we can't neutralize this toxic napqi, and then this molecule literally starts killing our liver cells. And resulting in liver necrosis very bad.

But yes, that is the reason for those warnings. Okay, So when you have acetaminifin toxicity, there's kind of four stages of disease that you can have. First, probably unsurprisingly, since this is a medicine you're ingesting, you can have nausea, vomiting, maybe some stomach pain a lot of times though in the early stages people might be entirely asymptomatic. But then what we start to see in terms of lab numbers

is that liver enzymes start to increase. These are a marker of liver damage, and this starts to show usually within twenty four hours, sometimes within twelve hours of ingestion, and then continue to increase over the next three to

five days. And this can become so severe depending on how much acetamenefin was ingested, that it can progress to fulminent liver failure, complete liver failure, which can result in things like hepatic encephalopathy, which is when your brain begins to swell and not function because of all of the other things that are building up in your body because

your liver has stopped working. We can see hyperbilirubinemia. This is an elevation in the breakdown products of our red blood cells that our liver is supposed to take care of. We can see lactic acidosis, or our blood becomes acidic. We can have profound hypoglycemia because our liver can't produce

more glucose. You can have thrombocytopenia, so we're not able to make platelets, which can lead to bleeding, and then this can progress to shock and eventually death or the need for a liver transplant.

and its metabolites are excreted. We pee out the metabolites of acetaminifin, So if these toxins build up, then it can end up affecting our kidneys as well. So this is obviously very severe and can and often is fatal if it's untreated. There is kind of an antidote, a treatment available. It's called n acetyl cysteine or KNACK, and it can prevent fulminent liver failure if it's given early enough.

Early enough usually means within eight hours of ingestion, but it can also help prevent like complete liver failure even if it's given later than that, depending on how severe the damage has been to begin with. So the question really is how much does it take to do this right? Like how much does it take to have these severe

side effects? And the answer to that question is why In more recent years, I think there has been a larger push I guess, or maybe chorus of papers that I found online saying maybe we should rethink how safe we consider acetam inifin most countries and most manufacturers list a maximum daily dose of a cetam in for adults,

not talking about children as four grams. So as an example, extra strength tile and all that you can buy in the US is five hundred milligrams, So that's like taking two of those four times a day or every six hours in a twenty four hour period. And a lot of the older literature used to cite, based on data from intentional acute overdoses, that we don't see toxicity to the liver until we get to doses like ten or twelve grams, so you'd have to take quite a lot

to overdose. But more recent data, especially data from people who perhaps weren't intentionally overdosing, but we're unintentionally taking slightly more than was recommended over the course of several days or a week, like maybe the time period in which you've got the flu. We have seen evidence of very severe hepatotoxicity or liver toxicity, including leading to death at much lower daily doses, like six or eight grams in twenty four hours, which is only a couple pills more

than the maximum recommended dose. So I'm going to talk a little bit more about this in the current event section because I think it's one of the main stories

with how we think about acetaminifin today. But this potentially small margin of error between the maximum daily recommended dose and a potentially incredibly toxic dose has become pretty controversial, especially because of how many other medicines acetamnafin can be found in that you may not know that acetamnafin is there, right right, So yeah, and that's all kind of just

the acute toxicity in terms of chronic use. It also used to be thought that acetamnifin overall was much safer than other things like eybiprofen or n sids, aspirin, et cetera, because we know those definitely increase the risk of GI bleeding. Turns out it's a little more complicated because acetamenifin definitely has a significantly lower risk of GI bleed than en sids, but it's not non existent because there might be some

peripheral COX activity going on, who knows. But there also is some mounting evidence that there's potential for other long term risks of large amounts of acetaminifin use over the long term, even if it's below that four gram threshold, and that is things like cardiovascular side effects, maybe a little increase in blood pressure. But in general, these data are not very well fleshed out at this point, which is really interesting considering how how long acetaminifin has been around,

which I know you'll talk about. Yeah, interesting, it's very interesting in general, it is so, Yeah, that sounds very scary when it comes to acute, especially overdose of acetaminifin. I don't want to fear monger because this is a medication that we have a ton of data to show that when it's used as directed, which is below that four gram threshold for adults, or some countries have further reduced it to three grams just to like increase that margin of error, it does remain a very safe medication

without this liver toxicity. Right.

Oh Malaria all the way back from our first season, and Aspirin from our second, which I know you.

pharmaceutical industry in the nineteenth century. So, the plant sources of both quinine and aspirin had been used for hundreds of years to treat fevers and pain, but it wasn't until the first decades of the eighteen hundreds that the active compounds quinine and the glycoside of salcilic acid were isolated, and that was thanks to huge advancements in the field of chemistry, and what this meant, What this isolation of these chemicals meant was that the effects of these two

compounds could be studied individually and in association with different dosages, and that they could be administered more accurately because you were giving a known amount of its pure form rather than a crude preparation. Because like the amount of quinine varies in different parts of the bark and from tree to tree and so on and so forth, so.

up to this task. In this quest to find alternative painkillers or fever reducers, chemists first directed their focus towards extracting common pounds from natural sources, figuring that there had to be more plant parts like willow bark or sinchona

bark that harbored potential drugs. But then with the birth and rise of industrial chemistry, chemists began to work on the synthetic production of drugs, mass producing compounds that they previously had to extract, or just creating new ones entirely.

side effects that acid analyde had. So once it started to become more widely sold, people were finding that it interfered with hemoglobin's ability to carry oxygen in the blood, and so they were like, we kind of need something that doesn't do this.

was called paracetamol. Story over right, the end, the end, Yeah, that never is no. In eighteen ninety three, a world renowned clinical pharmacologist named Joseph von Mehring ran some trials on this metabolite, paracetamol, comparing its efficacy and safety with exacs, fever reducers or painkillers, and he was like, hey, this is great. Paracetamol reduces fever and pain, but it's actually just as dangerous as acid analyide. It also interferes with

oxygen transport by hemoglobin. No one should sell it. It's not going to be a good replacement. Kind of weird, right, because we know that it doesn't do this right. And while yes, you talked about that it can be toxic in large amounts if not taken as instructed, von Mehring wasn't working with enormous doses, but like standard ones. So researchers today think that the paracetamol that he was using in these tests had been contaminated in some way, possibly

with like acid analyide or one of the previous steps. Interesting, but von Mehring had such a strong reputation that no one questioned his results for fifty years. Fifty years.

but yeah, fifty years. And I don't know what happened in the nineteen forties that prompted this, but around that time two researchers named Brody and Axelrod began a systematic study into paracetamol wow, and in nineteen forty eight they published a paper that outlined how paracetamol was actually the compound responsible for the fever reducing or pin reducing ability of acid analide, and importantly, it did not have the hemoglobin oxygen interfering effects that acid analyide had and that

von Mehring was mistaken. Yeah, paracetamol also had some advantages

over popular painkillers of the day. It could be given to kids as well as people with stomach ulcers, both for whom aspirin was a big no no. And Brody and Axelrod's papers on paracetamol were enough to convince the medical and scientific community that it was worth another shot and that it could and should be marketed, and so in the nineteen fifties it began to be sold, first generically in nineteen fifty three, and then as tailenol in the US in nineteen fifty five and as panadal in

Britain in nineteen fifty six. So hopefully that wasn't too confusing of an origin story. But I just I feel like it is so amazing that we have this thing at all. Yeah, And I wonder whether this kind of bizarre, accidental so many things had to happen origin story may play a role in like why we still don't know, because like this thing was just here's this random chemical that somebody is getting and.

the early nineteen eighties. Yeah, introducing the tailanol murders. Before I get started, I want to give everyone a content warning here that I will be talking about the deaths of several individuals and you can skip ahead. I don't really know, but like maybe twenty five thirty minutes to be on the safe side if.

to do. The tail Nall Murders began on September twenty ninth, nineteen eighty two, a regular Wednesday morning for most of the residents of the suburbs around Chicago. Early that morning, at around six fifteen am, a twelve year old named Mary Kellerman woke up with a bad head cold. She convinced her dad to let her stay home from school that day and went into the bathroom to take a couple of extra strength tylan all that her mom had

bought from the store the night before. Not more than a few seconds past when Mary's dad heard her coughing and then collapsing to the floor. He rushed in and found her on the ground, breathing shallowly and with her eyes fixed and dilated. He called the paramedics, but they weren't able to revive her. Mary's mom arrived home in time to see her only child being placed in an ambulance, and was held back from getting any closer to her.

Mary was in full cardiac arrest even before reaching the hospital, and this happy, go lucky, inquisitive kind and so very loved twelve year old was pronounced dead at nine fifty six am. This was a nightmare, and it was only the beginning. That same morning, around eleven am, seven year old Adam Janis, resident of nearby Arlington Heights, was out running errands with his wife, Teresa and their young kids.

This is the first hand account I mentioned. One of his stops was at a grocery store where he picked up, among other things, a bottle of extra strength tilanol. When he got home and put the groceries away, he opened the bottle of tailanol and swallowed a couple Within moments, he came out of the bathroom clutching his chest, breathing shallowly, and his wife saw that his eyes were fixed and dilated.

earlier in the day to ease her headache. She began to feel dizzy and collapsed almost immediately, experiencing seizure. After seizure, she was also taken to a nearby hospital, where she was put on life support. She died the next day. Going back to the Janis family, who had gathered at the hospital where they were informed of Adam's death, Adam's wife, parents, sister, brothers, and their wives decided to gather back at Adam and

Teresa's house to start planning his funeral. Adam's brother Stanley wanted to head back to his own house with his wife, Terry. They had just married three months ago. They hadn't even gotten the wedding pictures back yet because his back pain had started to flare up, but his mom convinced him to stay. When he and Terry got to Adam and Teresa's house, he said he was going to take a couple of tilan All for his back pain and headache

and asked if anyone else wanted to. Everyone else said no, except for his wife, Terry, who also had a headache. He grabbed the bottle that he found in Adam and Teresa's bathroom, took two for himself and gave two to Terry. Within moments, both Stanley and Terry began complaining of chest pain and collapsed again. The paramedics were called, and they were shocked when the call came in because it was the exact same address as just a few hours before, and when they got there, it was like the most

horrible deja vu. They found a frantic family huddled around Stanley and Terry, who were on the floor, breathing shallowly and with fixed and dilated eyes. What was happening? Remember, they thought that Adam might have had a massive heart attack, but it was next to impossible for two other young and healthy members of his family, one twenty five and one twenty to also have died of heart attacks within a few hours. Something was terrifyingly wrong. Oh yeah, sorry, I know that was a lot.

she collapsed. The paramedics, when they got there, attempted to revive her, and her friend mentioned the tilan al, but the doctors told Mary's family that they suspected a massive stroke. One more death would round out this horrifying day. Paula Prince's flight attendant for United stopped at a store after a long day of work and picked up a bottle

of tailanol. When she got home, she took a single capsule from her new bottle while getting ready for bed, and her sister and friend found her body two days later.

the situation was so unusual. Fire Lieutenant Chuck Kramer was one of the firefighters on the scene, and he suspected right away that something wasn't right, that these were not heart attacks, and that someone in public health should probably get involved as soon as possible, so he called his friend, the only public health official in the area, nurse Helen Jensen.

She rushed to the hospital and started asking the Janis family about their day, what they had eaten, where they went, and she learned that all three of the people who had gotten sick had taken tailand al just moments before, so she then went to their house to see if she could spot anything. She looked around, found the bottle of tailan al, counted them all out and found that six were missing, two for each person who had gotten sick.

Of course, no one believed her when she went back to the hospital and told a rep from the Cook County Medical Examiner's office that she thought the cases were linked to Thailand Al. She repeated herself several times, was met with skepticism each time and was like, you know what, Okay,

I'm going home, But her friend fied. Lieutenant Chuck Kramer, who had called her initially, he had learned of her suspicions, and he told a friend of his, another fire Lieutenant Phil Capitelli, who mentioned that Mary Kellerman, the twelve year old who died, had also taken tylnal moments before collapsing. That seemed like too much of a coincidence to Kramer, who called the hospital where the Janices were and told

their doctor, Thomas Kim, what he had found out. Doctor Kim was interested and had already suspected that the Janises had ingested some sort of poison, but this didn't seem like the other cases of paracetamol poisoning that he had treated in the past. For one, the symptoms were wildly different, and for two, paracetamol poisoning took much longer to show. There was only one poison he could think of that caused death so quickly after ingestion, cyanide.

But also apparently I read that only sixty percent of the population can even smell it, So like, whoa pretty amazing yeah. Yeah, And the blood tests from Stanley and Terry came back at one point thirty in the morning, and they showed an incredible amount of cyanide, certainly the cause of death. Later analysis would show that each pill in the Janis's bottle had an amount of cyanide three times what would take to kill someone.

you bought tailan All, throw it away? Whoa yeah, And amazingly, probably due to what seems like an incredible speed with which this medical mystery was solved, no other deaths occurred from the tainted bottles, and at least three other bottles were found, but it's likely there were more because so many people just simply threw them away.

how how do they do this? How simple? Like disturbingly simple. Today, when you buy a new bottle of thilenol or any other over the counter medication or anything, really it comes in tamper proof packaging in a sealed paper box, plastic wrapped lid, foil, seal over the top, several things that would make it apparent if someone else had opened the bottle before you. Back in nineteen eighty two, that type

of packaging did not exist yet. You could say, buy a couple of bottles of extra strength tile and all bring them home, take them out of the non glued box, unscrewed the cap, replace the acedum in afin inside the capsules with cyanide, put them back in the bottles, screw the cap back on, put the bottles back in those boxes, and then just walk into the store and put them back on the shelf without anyone realizing.

was solved. And I think in large part it's because the Janice family and how it was like, Okay, what is the commonality among these three individuals, and then but also like this fire lieutenant talking to this fire lieutenant calling this particular nurse who just like had that like detective work down. It's just amazing that.

the other person. And so then how many other fire chiefs did they call or like whoever it was that they called from the other suburbs and places like I mean, because all of these would have been very like dramatic at whatever hospital these people presented to, right, But it's still very amazing that that that information got passed around so rapidly to be able to identify all of these and then really pinpoint it so that you could get the word out everywhere and not just in the one neighborhood.

Ough it's just yeah, but yeah, So even though they figured this out so quickly, there were two big questions that remained.

Jim Lewis, who had ties to the Chicagoland area. At first, investigators thought that he was probably just an opportunist trying to profit off of these deaths, but they dug a little deeper and found that he had been charged in but not convicted, of a murder in Kansas City four years prior, showing that he was potentially capable of violence, and he was currently under investigation for a credit card scam. He was tried for extortion, and while he awaited sent

and sing he reached out. Jim Lewis reached out to an FBI agent on the case and offered his expertise, drawing detailed sketch after detailed sketch of the logistics of poisoning the capsules, like how you would go into this store versus this store, And how you would empty out the aceta minifin with cyanide and replace it with cyanide, and all of these things, and like troubleshooting, what would happen if something went wrong? What would you do in

this case versus this case? He wanted to read all the case files, like get really involved, A little bit suspect, right, circumstantial,

but anyway. Ultimately, Lewis was sentenced to ten years in prison for the extortion letter, plus time for the credit card scam, and when he was released in nineteen ninety five, the FBI still had him in mind for the murders, continuing to monitor him and even running an undercover sting in two thousand and seven where an agent posed as someone writing a book about the murders and offering to clear his name. They collected lots of strong circumstantial evidence

against Lewis for one motive. So he had a young daughter named Tony who died after a heart surgery her second, and an autopsy revealed that the sutures that had been used in her first heart surgery were made by Johnson, and Johnson possibly faulty, possibly contributing to her death during the second heart surgery. So maybe investigators thought that he wanted to take revenge on the company in this way. Number two is that he allegedly wanted to start a

pill press business, like making pills. Number three, his timeline for being out of town and writing the letter kind of changed, so like he definitely wrote the letter, but he like when.

that the public had in these products. Two months after the murders, tamperproof packaging was introduced, and in nineteen eighty three it became a federal offense to tamper with consumer products. By nineteen eighty nine, the FDA introduced guidelines for all consumer products to have tamperproof packaging. Still, it took a long time for the public to trust tilanol and other medications again. And one of the sort of like searing things I think about this story about these cases is

the horror of it all. Right, Like these these people's lives were just ripped away from them, like within moments, who were just completely out of the blue doing nothing and then one day attacked for no reason whatsoever, and then just like that was it. It's done, And it

just feels like such a senseless and horrible thing. And I think the horror of it all and how scary and how this was able to happen is really you can see that in just how rapidly things changed and how much things changed in terms of like it is really, I mean, there was a before and after very starkly different in terms of like tamper proof packaging, how we approach that, how we view safety in stores, protections for consumers. And it is horrible that these deaths had to spur

that on. And it's also horrible that their family members and their friends and their loved ones still don't have the resolution and closure in the form of justice.

It also, in many countries is one of the most common causes of both intentional and unintentional overdose admissions to hospitals, and in the US and the UK and Europe, one of the most common causes of acute liver failure as well. I could not get solid data on the exact number of overdoses or deaths, or even liver transplants that are

due to acetominifin toxicity worldwide. Most sources that I read for the US data cited about fifty six thousand overdoses that result in emergency department visits and up to five hundred deaths annually in the US, But from what I can tell, that's data from like two thousand and five that's just still cited everywhere, so I don't know if there's more up to date data, and it seems like that might not be the most accurate because some of the numbers that I saw from the UK are quite

significantly higher in terms of overdoses, like eighty to ninety thousand hospitalizations but between one hundred and fifty two hundred deaths. And obviously our population sizes are very different, so it's really hard to say how many people this is affecting worldwide, but certainly it's not an insignificant number of people that are becoming very sick or potentially dying from liver toxicity

associated with the setominifin. However, there's also tens of millions of doses that are taken every single day across the globe. This is an incredibly ubiquitous medication. So again, this is something that when taken in the dosages that are recommended

or below the maximum recommended doses, is quite safe. But I think that this idea of how do we determine what is safe and what a maximum dose should be, and how do we label medications and package medications to let people know what is safe and what is potentially dangerous about them. Is kind of where the story of a cetamnifin or paracetamol is going and is likely to

continue to go in the future. There was a really comprehensive, very very very long article published by pro Publica from twenty thirteen, so it's fairly old now, but I found it really interesting because it really focused on the pushback from manufacturers on changing anything about the way that we label a cetamnifin to let people know that it is potentially toxic and specifically what that toxicity might look like.

Because a cetamenifin toxicity because it can build up over several days, you might not know that it's happening while it's happening, so it could be asymptomatic, right, And there's been a lot of push push back or laxity from like the FDA in terms of implementing stricter safety measures, which we've seen implemented in other countries like the UK, which has much stricter requirements on how many pills can be in a package and things like that, with mixed

results on whether that's actually decreased overdoses overall, but at least there's like public health attempts, if that makes sense. So I think that that's kind of an important part of the estate of benefit story is really not only understanding the mechanisms, like how is this really working in our bodies? Are there other like chronic effects that we might not be aware of that are happening or are

they only happening at very high doses? How do we label this medicine that's so ubiquitous, right, It's in so many of our other like mixed formula drugs that are available over the counter and in some cases in relatively high quantities that you might not realize altogether add up to more than four grams? Are there other public health measures that could be implemented that would reduce the risk

of unintentional overdoses, especially as well as intentional overdoses. So I think that that's kind of where the future of acetaminifin research and public health is likely going to go.

And I think for me, what it really highlights is something that we've talked about actually kind of a lot on this podcast, and that is that the dose makes the poison right, Yes, literally nothing no medication, antibiotics, anti fever, pain medication, gas, medication, constipation, medication, any medicine, any drug, any thing that you consume or put into your body has pros and cons It has the potential to help us and has the potential to have undesirable side effects.

And so all of medicine is balancing these and making sure that the benefits outweigh the real or potential harms. And so I think that maybe for acetaminifin that there's been a long period of just focusing on all of the benefits and the fact that it is safer than en SAIDs in certain respects. It is safer than end SAIDs in terms of risk of GI side effects or even kidney side effects, but that doesn't mean that it's

without its potential for very serious harm. And so how do we then balance that both on an individual level and also on a population level from a public health perspective. Yeah, yeah, So that's paraceta, all acetominifits sources.

a review of known and novel mechanis of action. I thought that was a great overview, but there's a ton more and I will link to that pro Publica article if you want to dig deep on all of that business. So we'll post all of our sources from this episode and all of our previous episodes and future episodes on our website, This podcast will Kill You dot Com.