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Tylenol: Safe painkiller, or drug of hepatic destruction?

What do Tylenol, Excedrin Extra Strength, Nyquil Cold & Flu, Vicodin, and Anacin Aspirin Free have in common? They all contain the drug acetaminophen. Taking multiple acetaminophen-containing drugs can be risky: while acetaminophen is safe when used at appropriate doses, at excessive doses, it is highly toxic to the liver. Take enough, and you’ll almost certainly end up hospitalized with liver failure. Acetaminophen poisonings, whether intentional or not, are a considerable public health issue. In the USA, poisonings from this drug alone result in 56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year. [PDF] This makes acetaminophen responsible for more overdoses, and overdose deaths [PDF], than any other pharmaceutical product.

Last week, Johnson & Johnson announced that it’s lowering the maximum recommended daily dose for its flagship analgesic, Extra Strength Tylenol, from 8 tablets per day (4000mg) to 6 tablets per day (3000mg). Why? According to the manufacturer,

The change is designed to help encourage appropriate acetaminophen use and reduce the risk of accidental overdose.


What’s an appropriate acetaminophen dose?

The dosage of any drug is based in part on its therapeutic window — the difference between the dose needed to cause a beneficial effect, and that which causes unwanted effects. In the case of acetaminophen, the limitation is how acetaminophen is eliminated from the body. Once ingested, acetaminophen is quickly absorbed from the gastrointestinal tract into the bloodstream. About 25% of the drug is immediately metabolized by the liver because of the first-pass effect. And the liver acts on the rest as it circulates through the body. Liver metabolism involves converting acetaminophen into substances (metabolites) that are easier to eliminate by the kidneys — and that’s where the risk of toxicity comes from.

Multiple liver enzymes can act on acetaminophen. The main metabolic pathways, sulfation and glucuronidatation, transform acetaminophen into harmless products that can then be excreted in the urine. In overdosage situations, however, these pathways become saturated, and eventually exhausted — so other metabolic pathways kick in. Unfortunately, these other pathways create toxic versions of acetaminophen that attach to, and destroy, liver cells. So at normal doses, acetaminophen causes no toxicity. At high doses, liver injury is almost a certainty. This chart illustrates the science of metabolism and toxicity: blue is good, and red is bad.

(Paracetamol is another name for acetaminophen.)

What leads to poisonings?

While many acetaminophen overdoses are intentional poisonings, a substantial number of cases are unintentional. In adults, the maximum recommended daily dose has traditionally been 4000mg. That’s eight extra-strength (500 mg) Tylenol tablets, or twelve regular-strength (325 mg) tablets.  A single dose of 7,500mg can cause liver injury, and consumption of 10,000 to 15,000 mg can be fatal. It’s important to note that 4000mg is the maximum daily dose from all sources — and that’s where many accidental poisonings come from. Combining cough and cold products, or taking too many painkillers, and bumping your total daily dose slightly over 4000mg in a single 24 hour period is unlikely to cause any harm. But take enough at once, or take regular moderately excessive amounts (say in the case of someone abusing Vicodin, Percocet, or even cough syrup), and unplanned overdoses can result. Chronic consumption of acetaminophen is is not uncommon: I’ve seen patients taking well over a dozen Percocet per day, for weeks or months — pushing acetaminophen consumption into the toxic range. They are surprised when I tell them my primary concern isn’t the narcotic consumption, but rather the huge amount of acetaminophen they’re consuming daily, which is almost certainly damaging their liver.

In 2009, the FDA held a series of hearings to address this issue of acetaminophen toxicity. (Harriet Hall covered it then.) It’s not a problem unique to J&J’s Tylenol. Acetaminophen is in hundreds of prescription and non-prescription products, and is used at all stages in life, starting in infancy: 28 billion doses of acetaminophen were consumed by Americans in 2005. Besides fever, headaches, and other everyday aches and pains, acetaminophen is the usual first drug of choice for treating chronic conditions like osteoarthritis. And hydrocodone-acetaminophen combination drugs (e.g., Vicodin) are among the most frequently prescribed drugs.

The FDA’s hearings resulted in an  expert panel making several recommendations, including advice that the maximum recommended daily dose of acetaminophen should be reduced, to lower the likelihood that patients will exceed a safe daily dose. This recommendation was made despite some advice (PDF) to the contrary. So while there remains some debate about the toxic dose, it was felt this measure would reduce the incidence of poisoning.

Unexpected consequences?

From a public health perspective, we should try to reduce the risk of acetaminophen poisoning. Cutting the maximum daily dose of Tylenol Extra Strength should reduce the risk of poisoning in the event it’s combined with other acetaminophen-containing drugs. There’s even some evidence that suggests that 4000mg per day for prolonged periods may cause elevations in liver enzymes — data which led to the American Liver Foundation recommending (PDF) the maximum chronic dose should be 3000mg per day. So there may be a clinical rationale, too. But changing the maximum dose won’t mean much to consumers that don’t read the label. And from the individual patient perspective, forcing a hard maximum of 3000mg per day for all patients may have unwanted consequences, too. To start, you may need to take 650-1000mg of acetaminophen at a time to achieve analgesic effects beyond placebo. So achieving prolonged pain control, while also not exceeding 3000mg per day, may be difficult. Yet higher doses could be preferable to alternatives, such as anti-inflammatory drugs, or narcotics, especially when used regularly, for chronic conditions. So will the dose change have any measurable effect? Here’s your control group: The maximum dose isn’t changing in Canada.

Conclusion

Acetaminophen is a remarkably safe and effective drug when taken at appropriate doses, yet it is also the cause of hundreds of deaths per year. Manufacturers are now acting, based on the FDA’s advice, with the intent of reducing the chance of accidental poisoning. The pragmatic approach? Read labels and be cautious when combining different over-the-counter drugs. For most adults, keeping daily consumption below 4000mg is the safest approach to minimizing risk.  And in some cases, a maximum of 3000mg may be more appropriate. But these are general approaches, that may not appropriate for everyone. A maximum dose of 3000mg make make sense at the population level, but may be problematic in terms of individual pain control. Regardless of the dose, if you regularly take high doses of acetaminophen, either alone or as a combination of products, a discussion with a health professional to discuss the risks and benefits may be warranted.

 

Posted in: Pharmaceuticals, Politics and Regulation, Science and Medicine

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44 thoughts on “Tylenol: Safe painkiller, or drug of hepatic destruction?

  1. kirkmc says:

    Well, at least it’s safer than aspirin or other NSAIDs…

  2. Scott Young says:

    Why not package it with appropriate amounts of N-acetylcysteine or L-cysteine or similar to reduce the likelihood of toxicity? If possible, wouldn’t that also be a selling point?

  3. Rick says:

    What about the affect of alcohol consumption and acetaminophen? I have always warned friends that they should never mix the two or take APAP for a hangover. I remember reading something on this several years ago, and know that both act on the liver, but is my assumption based more myth than science?

  4. cervantes says:

    The only reason they put acetaminophen in Vicodin is so that addicts will end up injuring or killing themselves if they take too much of it. That is beyond insane.

    The thing with acetaminophen and alcohol is a bit complicated, but basically, people who drink habitually and then stop for a while or lighten up too much are at highly elevated risk of toxicity, because you have an induced metabolic pathway that’s no longer occupied by the ethanol. So yes, that’s one more danger.

    Personally, I don’t think acetaminophen is safe and I really can’t justify its use except for people who really can’t take aspirin or NSAIDs. It ought to be a last resort, not a first resort. Just sayin’.

  5. windriven says:

    “The FDA’s hearings resulted in an expert panel making several recommendations, including advice that the maximum recommended daily dose of acetaminophen should be reduced, to lower the likelihood that patients will exceed a safe daily dose. ”

    If as stated above, 4000mg is the safe maximum daily drug then reducing the recommended daily dose to 3000mg reminds me of people who set their clocks 10 minutes ahead so they won’t be late.

    If the safe dose is 4000mg from all sources then say so on the label. Lying about the safe dose is neither ethical nor prudent. The message then becomes that IFUs are bullrip so there is no need to take them seriously. How stupid is that?

  6. Scott says:

    They do say so on the label – in fact they say not to use any other acetaminophen-containing products AT ALL. Obviously not as effective as we might like.

    I don’t see a way to really address the cross-product problem except via education, which will be quite difficult to accomplish. People need to know what they use that contains acetaminophen, which they mostly don’t.

  7. kirkmc says:

    “Personally, I don’t think acetaminophen is safe and I really can’t justify its use except for people who really can’t take aspirin or NSAIDs. It ought to be a last resort, not a first resort.”

    Really? Aspirin and NSAIDs are more dangerous, leading to far more deaths. Why do you say the above?

    (FWIW, I can’t take aspirin or NSAIDs…)

  8. windriven says:

    I understand that the label states the maximum dose from all sources, Scott. My point is that lying about the maximum safe dose, saying that it is something lower, is wrong and counterproductive on just about every level. If people don’t read the label then it doesn’t matter what the label says. Those who do read the label deserve to be given accurate information that they can trust.

  9. Scott says:

    If stating the maximum dose as 4000mg from all sources leads to overdose, then it’s not actually safe to set that as the maximum dose. Seriously, it’s not like there’s some bright-line “right answer.”

    Considering the odds that people will exceed the stated maximum when setting that maximum is not “lying.” It’s perfectly prudent and reasonable.

  10. Jimmylegs says:

    @Rick:
    According to drugs.com (seems like a reliable source) “Ask a doctor before taking acetaminophen if you drink more than 3 alcoholic beverages per day, and never take more than 2 grams (2000 mg) of acetaminophen per day.”

    “up to 2,000 mg per day if drinking alcohol” Was in the wiki article for apap but was cited from drugs.com (the quote above).

    @wind:
    I know I read the label for any drugs I take, heck I even read the entire book (paper) you get from prescriptions. However my actions are not the same as everyone elses, so in order to protect people that go over label (accident or not) from injury they can reduce the max dosage.

    Even if the label is changed to 3000mg if your doctor says it is safe to go to 4000mg I would trust his/her opinion. But sadly people sometimes don’t listen and go over, which is how we get issues such as this.

  11. Angora Rabbit says:

    @windriven, I hear what you’re saying but it isn’t lying. To rephrase what Scott said, the 4000 mg value is based on a population’s response as a whole. But within that population there is individual variability. When we set a toxicity threshold, it needs to account for that variability as well as other modifying factors that we don’t know about. These variables can include alcohol use, intakes from other sources, and genetic variability in the efficiency of the glucuronidases and sulfanation reactions that dispose of the acetaminophen.

    So a toxicity threshold isn’t a line in the sand. It’s a soft value estimate that is supposed to be a safety bumper-distance away from what the best data suggest is the toxic dose. And we shift the line as better data come in about exposure risks and other modifying factors.

    Does this make sense?

  12. cervantes says:

    KirkMc –

    evidence? data?

  13. kirkmc says:

    cervantes:

    Seriously? You don’t know this?

    http://www.nature.com/ajg/journal/v100/n8/full/ajg2005305a.html

  14. Nescio says:

    Scott Young,

    I was taught that there are two reasons that the antidote to acetaminophen is not added to the tablets, firstly the added cost, secondly they smell sulfurous, which customers don’t like. You could coat the tablets to eliminate that, but that also adds to the cost. Personally I think it should be illegal to sell the stuff without the antidote.

    I spent many years working in UK clinical biochemistry, measuring blood acetaminophen levels on people who had taken (mostly deliberate) overdoses. There is a window of about 48 hours during which the antidote (methionine or n-acetylcysteine) is effective, and a cut-off level at which treatment is recommended, depending on how long since the drug was ingested.

    Not infrequently someone would take a massive overdose mixed with alcohol, go to sleep, and wake up having decided that life wasn’t so bad after all. Then a few days later they would go into acute hepatic failure. There isn’t much you can do at that point apart from hope that a liver transplant donor becomes available. Dying from liver failure is not a pleasant way to go.

    Incidentally, when I first started working in labs the method involved doing an ether extraction and was long-winded and complicated. Then some of my colleagues developed an enzymatic method that was much quicker and easier.

    How did they find an enzyme that would break down acetaminophen? Simple – they surreptitiously took soil samples from around a factory that made the drug, and found bacteria that could eat the stuff. Then it was a simple matter of culturing large quantities, extracting the enzyme, and linking it to an NADH reaction and a color change. That made a large difference to the management of overdoses, and certainly made my life a lot easier.

  15. Reductionist Nurse says:

    I think this new recommendation is an awful idea for several reasons, some already outlined in far better words than mine.

    1) Hydrocodone, one of the most effective moderate-to-severe painkillers, is only available in combination with other drugs, and by far most often with APAP. In my mind, and as given in examples, this is one of the causes of the overdose problems. As we all know, typically the more effective something is, the higher potential it has for abuse. This feels like the people in charge are merely addressing the result of a problem and not the real cause.

    2) Consumers don’t like to read labels. They drink while taking vicodin. That fact negates any safe dose guidelines. Its pretty much bad for you, period.

    3) A pragmatic opinion should not take priority over what the data says. Alt-med wackaloons will have a field day with this. I haven’t looked on Naturalnews.fraud yet but I can already bet Mike Adams is heralding this as a victory or “proof” that acetaminophen is more dangerous then it actually is.

    4) You can’t protect people from themselves. You can educate and we can all do our part to follow best practice, but at some point darwin takes care of the rest. Smoking is bad, people still smoke. Excess simple cards are bad, T2DM is still rising. Prilosec OTC, need I say more?

  16. “Ask a doctor before taking acetaminophen if you drink more than 3 alcoholic beverages per day”

    You have to worry about all the different sources of acetaminophen; maybe you should also consider the different sources of alcohol as well.

    One of those alcoholic beverages may be cough syrup with both alcohol and acetaminophen in it.

  17. Skepgineer says:

    Why not just require a prescription for Tylenol? NSAIDs are safer but some people can’t take them.

  18. cervantes says:

    Kirkmc –what the article you linked to says is that widely publicized estimates of deaths attributable to NSAIDS are probably highly exaggerated.

    I must also point out that injury from NSAIDS and aspirin occurs only with chronic use, as in arthritis. Acetaminophen is not anti-inflammatory and is of much less use in these conditions — but it causes acute poisoning with only occasional use. For occasional use, aspirin and NSAIDs are much safer. So this is a completely irrelevant comparison.

  19. icewings27 says:

    Reductionist Nurse is right about Vicodin – People who abuse painkillers are going to do so regardless of the risks, and the fact that combining hydrocodone and acetaminophen INCREASES the risk of overdose should be examined.

    I can buy most OTC drugs in single-medication formulas (e.g. pseudoephedrine, acetaminophen, diphenhydramine), or in a multiple-medication mixture (e.g. Nyquil). Why shouldn’t prescription medications offer the same consumer choice?

    Postscript: When my sister OD’d on Vicodin, alcohol, and Valium, the doctors were way more concerned about the acetaminophen than anything else she ingested. Who’d have thunk a little OTC drug like that could be so potentially dangerous?

  20. CarolM says:

    Has anyone noticed a slight sedative effect from tylenol? Once in a while I take one 325mg to help me sleep and it does seem to help.

    Still, I use it rarely. It must have been 20 years ago I first started reading and hearing about the risk of liver failure. News mags and 60 Minutes did stories on it. Yet many people still don’t know. Some friends of mine who are big partiers would each pop 4 extra strength before a night of drinking. They blew me off as a party pooper when I brought it up.

  21. passionlessDrone says:

    Hi Scott (or anyone) –

    I’d be curious on your thoughts on the potential relationship between acetaminophen and asthma, which seems to have up and down signals from several studies.

    Thanks.

    - pD

  22. kirkmc says:

    Cervantes, even at the low end of the scale, there are far more deaths and hospitalizations from NSAIDs and aspirin than from acetominophen.

  23. windriven says:

    @ReductionistNurse

    “You can’t protect people from themselves. You can educate and we can all do our part to follow best practice, but at some point darwin takes care of the rest. ”

    Thank you.

    I wrote a couple of responses and deleted them before I sent them because they were … incendiary. You’ve made the point well.

  24. Intraneural says:

    I am an anesthesiologist and an acute pain medicine physician and I love to use tylenol as an adjunct when treating perioperative pain. My personal feelings on reducing the maximum dose of APAP is that it should not be done. As far as I can remember when I researched this topic in the past- the major study that the 4 gram limit was based on was a large retrospective study looking at a very large number (forgive me I cannot remember specifics) in the tens of thousands that was performed at the University of Pittsburgh. I will try to find the reference later. In it they found around 150 pts or so that developed liver failure and all these pts received doses of around 7 gm or higher. As i recall the 4 gm limit was to provide a large buffer. All the patients had multiple morbidities. Having said that of course mixing with alchohol or for long term use can be dangerous.

    From my experience (the most dangerous phrase in medicine per Dr. Crislip!) APAP is a great adjunct in perioperative pain. I particularly like the iv APAP now availabel at my institution. It now allows us to give an adjunct in npo pts. One must consider that although there is a risk to APAP, when used appropriately it is a great way to reduce opioid consumption. If one balances its appropriate use with the risks associated with narcotics (respiratory depression/arrest, pruritis, constipation, n/v, immune supression and the new data of increased breast CA recurrence, hyperalgesia) then one cannot ignore its benefits. Any medication that is able to reduce opioid consumption is a benefit in my book.

    I think a new great question, in the US at least, is if there will be an increased risk of hepatotoxicity with the iv formulation. I suspect no, but we will have to see.

    Reducing the dose allowed will only decrease APAP effectiveness. It will provide increased scrutiny on physicians and could pr\otentially increase malpractice risk on physicians trying to provide analgesia to their patients. A true effective dose PO is 1000 mg, 650 is inadequete in most patients. Its effect tends to last 4-6 hours which leads to a 4-6 hour gap in the day if trying to provide a 1 gm q 6 hour dose. As for limiting the max dose for outpatient I question whether there will be any true decrease in hepatotoxicity since most people do not read labels.

  25. Ken Hamer says:

    While it may be true that some people “won’t” read the label, I suspect it’s also true that even more people “can’t” read the label. There may be some cases of people not being able to understand what the label means, but even I now have difficulty reading the extremely small type on the package, the bottle, and often even the paper insert. I think that some of this problem could be resolved by mandating a minimum text size on all labelling. Either that, or include a microscope with each package.

    My other frustration is with “all-in-one” medications. I’m guessing that most people don’t realize they are consuming Tylenol when they take cough syrup. Likewise, if I want a muscle relaxant for my back, then that’s all I want. If also want a pain killer, then I’ll make that decision on my own as well, thank you very much. It’s annoying to have to hunt for what it is you want/need, without taking “all this other stuff too!” It might be a great marketing tool (“this medicine will save your marriage”) but I’m not certain it’s a good thing health-wise.

  26. aeauooo says:

    Like icewings27, I buy most of my OTCs in single-drug formulas and avoid combination products (guaifenesin + dextromethorphan cough syrup being the exception to my rule).

    A strategy that might decrease unintentional acetaminophen overdoses and increase public awareness of the problem would be for manufacturers to market their OTC products as “acetaminophen free.”

    With prescription medications, there is at least an opportunity for prescribing providers and pharmacists to discuss the risk of overdose with acetaminophen-containing drugs.

  27. Intraneural says:

    I do like the fact that percocet (apap and oxycodone) does come without the apap. I wish that vicodin was available in pure hydrocodone also. I do however suspect that many patients would not take the Tylenol separately though. I have had many calls where the patient refuses to take either apap or NSAIDs for uncontrolled post op pain at home because they perceive that Motrin or Tylenol won’t work because their pain is too severe. What I had always heard while in training that the apap was added because of this perception by many patients. But as an adjunct these “less powerful” painkillers work great.

    Also, I wonder what person would even bother to add up how much Tylenol they are getting in each medication anyway to determine if they have reached the max recommended dose?

  28. aeauooo says:

    “they perceive that Motrin or Tylenol won’t work because their pain is too severe.”

    I have found that most people are surprised by how well their pain is controlled with a dose of acetaminophen on top of an opioid.

    “[Anecdotes] count for wind only. We bunch them and use them for head winds in retarding the ships of improper people, but it takes so many of them to make an impression that we cannot allow anything for their use.” (apologies to Mark Twain).

  29. Dpeabody says:

    I think it may be worth noting for future articles that tylenol means nothing to most people from the uk, they are moch more familiar with the term paracetamol.

  30. elburto says:

    aeauooo- I personally find that my morphine seems to work much better with a gram of paracetamol on the side. Also, for classic migraine (when triptans are impractical at that time) Migraleve (total dose 1g paracetamol and about 15mg codeine) + 330ml of Pepsi, can provide very quick relief. OTOH one aspirin will trigger an almost intractable asthma attack, and NSAIDs give me profuse GI bleeding.

    Here in the UK it’s rare to see paracetamol sold/dispensed at doses under 500mg. That’s reserved for off the shelf preparations that also contain aspirin and caffeine, the ‘flu plus’ preparations. An. American acquaintance had Tylenol shipped over here by her parents, as she was convinced that “huge doses” of generic paracetamol (again, 1g four times a day) were at the same time deadly, and totally ineffective.

    WRT overdose – I used to do phone triage for a GP out of hours service (nights, weekends, holidays). The people most likely to overdose on paracetamol were those with dental pain, followed closely by children dosed incorrectly by a tired parent. Obviously we did deal with deliberate OD as well. A caller rang up one tuesday night, worried about her 19 year old son. He’d para-suicided on the saturday, in an attempt to stop his girlfriend leaving him. His mother explained that as he’d seemed fine after “sleeping it off” they’d decided to “put it in the past”, but that he was now vomiting and jaundiced. Five hours after I took that call, the lad was “in the past”. I watched several experienced doctors and nurses cry that night. Better education is the answer. People tend to think that an overdose means instant death. A teen soap opera (Hollyoaks) ran a storyline about the same issue a few years ago, but I can’t remember seeing any concerted effort to educate people about taking too much.

  31. DBonez5150 says:

    I always understood that opioids were combined with acetaminophen because of the moderate-to-high synergistic effect. It would make sense and explain why patients mixing the two have good response. It would also explain why Vicodin is prepared like it is and why it’s so effective.

  32. aeauooo says:

    @elburto

    “Migraleve (total dose 1g paracetamol and about 15mg codeine) + 330ml of Pepsi, can provide very quick relief.”

    I keep dark chocolate in my desk drawer at work – for medicinal use only.

    “Here in the UK it’s rare to see paracetamol sold/dispensed at doses under 500mg.”

    I prefer buying 325 mg tablets because it gives me more dosing flexibility, but they’re not always easy to find.

  33. Intraneural says:

    @dbones- it does make for a synergistic effect. The issue I have with vicodin and percocet though is that one either doesn’t reach the most effective analgesic dose of the apap, or one risks going over the recommended dose. At least inpatient I prefer keeping them separate. APAP is most effective when given 1000 mg four times daily. To try and administer that with prn vicodin or percocet makes for a more comPlex dosing regimen. Percocet is great because you have the option of using just oxycodone but because of genetic variability some people reapond better to hydrocodone which is not separate. Oxycodone also tends to make the elderly more confused so a separate hydrocodone would be great in this population with a Max dose apap to help decrease narcotic need.

  34. DBonez5150 says:

    @Intraneural

    There is always Norco, and while still a mix of hydrocodone/APAP, it’s higher ratio 10/325 gives better dose-control options with APAP.

  35. Toiletman says:

    Paracetamol, as we call it here in the old world, seems to have more advantages than disadvantages in my opinion and according to my experiences. NSAIDs can’t be taken by many people such as those with IBDs such as myself and in most countries, paracetamol/acetominophen is the only prescription free alternative. Personally I just wonder why there aren’t any extended release ones, especially for those combined with opioids where such formulas would lower the addiction risk (I never understood why House MD would not just take a once daily extended release dose of opioids instead of the unstable flow of vicodin inevitably leading to addiction but well maybe for plot purposes :D). It really does well in lowering the necessary opioid dose.

  36. Intraneural says:

    @toiletman Unfortunately an extended release paracetamol would be useless because the analgesic effect depends on achieving high enough plasma levels.

    1. Scott Gavura says:

      There is an extended-release version of acetaminophen/paracetamol on the market.They’re 650mg tablets, and a labelled 8hr duration of action.

  37. Toiletman says:

    And a drug that releases part of its paracetamol instantly and the rest in a way that each about each 500mg(or more) is released in about 6 hours (simplyfying that it takes 6 hours halflife)? There are other drugs with such a mechanism (ADHD medication for example). Or does paracetamol has any uncommon properties that prevent that?

  38. Intraneural says:

    Scott, how effective is the extended release since it is such a low dose and the blood levels can’t be near therapeutic with first pass metabolism?

  39. JPZ says:

    @Nescio

    I spoke to the former Medical Director for the Tylenol brand, and he pointed out the “rotten egg” smell of N-acetylcysteine as being the drawback on adding it to Tylenol. Personally, I still think there should be a way to overcome the smell problem, and cost is a matter of volume (volume driving newer and cheaper synthesis methods too).

  40. Calli Arcale says:

    One thing I’ve wondered is why this label is on diphenhydramine but not acetominophen:

    “Do not use this drug at the same time as any other products containing diphenhydramine, even topical one.”

    (Or words to that effect.) Diphenhydramine is an antihistamine (Benadryl) notorious for causing drowsiness. Taking too much is bad; it can actually cause you to lose consciousness or even stop breathing. I don’t recall seeing a similar notice on Tylenol. I *do* recall seeing a similar notice on prescription drugs which contained Tylenol, but not the OTC stuff.

  41. Scott says:

    I see such notices on all the acetaminophen-containing OTC meds I have around.

  42. trrll says:

    Adding acetaminophen to opiates is nuts. It makes it harder to adjust the dose appropriately (particularly in chronic pain where opiod tolerance is an issue), and greatly increases overdose risk. But the greater insanity is in the regulations that have caused the pure opiate formulations to be more strictly regulated than the combination products. The idea that combination products can be less stringently regulated due to the risk of acetaminophen toxicity ignores the reality of drug abuse–these combination products are widely abused by young adolescents who filch them from parental medicine cabinets and take them by the handful and who mostly have never heard of acetaminophen toxicity. There even seems to have developed a street myth that the acetaminophen enhances the intoxicating effect of the opiod, so some kids will actually take Tylenol on top of Vicodin.

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