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Acetaminophen: Still the pain reliever you should trust?

Recently ProPublica and This American Life (TAL) released the results of an investigation into acetaminophen, the active ingredient in Tylenol. TAL devoted an entire episode to the issue, and ProPublica has published several stories on acetaminophen’s toxicity, how it can cause harm, and how it is regulated.

The investigation summarizes the key “Takeaways” as follows:

  • 150 Americans die per year from accidental acetaminophen overdoses
  • The safety margin (safe dose vs. toxic dose) with acetaminophen is small
  • Both the FDA and the manufacturer, McNeil, have known about the toxicity for years
  • For over 30 years the FDA has failed to implement measures to reduce the risk of harms it knew existed
  • The manufacturer has taken steps to protect consumers but has also opposed other safety measures

While Tylenol is a single brand out of hundreds of prescription and non-prescription products that contain acetaminophen as an active ingredient, it is the brand most closely associated with the chemical. Amazingly for a drug that has no patent and lots of competition, Tylenol products are estimated to make up half of all non-prescription acetaminophen sales in the US, a testament to the power and effectiveness of marketing. (It’s also a clear refutation to alt-med arguments that unpatented products can’t be profitable, or aren’t of interest to the pharmaceutical industry.) While much of the focus of the investigation centers on the corporate behavior of Tylenol’s manufacturer, McNeil, (a division of Johnson & Johnson), it is important to keep in mind that no single company is responsible for acetaminophen sales and marketing.

Before diving into the investigation and its findings, a review of the pharmacology and toxicity of acetaminophen will help with the context. (More detail, if you’re interested, is contained in a prior post.) Acetaminophen is a drug that has analgesic (pain relief) and antipyretic (fever-reduction) actions. Unlike non-steroidal anti-inflammatory drugs (NSAIDs) like acetylsalicylic acid (ASA, aspirin), ibuprofen (Advil) and naproxen (Aleve), acetaminophen has no effect on prostaglandin synthesis – so it is not an anti-inflammatory. This lack of anti-inflammatory action gives it a completely different side effects profile. Unlike NSAIDs, acetaminophen is unlikely to cause gastrointestinal ulcers, blood disorders, or kidney problems, all common with NSAIDs. Nor does acetaminophen increase the risk of cardiovascular events such as heart attacks and strokes, like some NSAIDs. Compared to NSAIDs, acetaminophen also has few interactions with other drugs, so it can safely be used for pain relief in those on multiple medications, or with other medical conditions where other pain relievers might have unwanted effects. Acetaminophen is not a narcotic, and provides a non-addictive alternative for managing chronic pain issues. It can also be used during pregnancy, and while breastfeeding. Finally, at the recommended dose, acetaminophen is almost completely free of significant side effects. This can be contrasted with NSAIDs, that cause a considerable number of drug-related hospitalizations each year. The problem with acetaminophen appears when an excessive dose is taken. And in that situation, acetaminophen is much worse than any NSAID.

The body eliminates acetaminophen through the action of liver enzymes that converts the base drug into substances (metabolites) that are easier to for the kidneys to filter and excrete. In overdose situations, this system fails catastrophically. We are physiologically able to safely metabolize a small amount of acetaminophen at a time – about 4,000mg in a 24 hour period for adults is generally considered the safe upper limit. The two main metabolic paths are sulfation and glucuronidation. These paths can be exhausted and overwhelmed in overdose situations, which is when other enzymes take over. N-hydroxylation creates a chemical compound that causes liver damage. In the diagram below: blue is good, and red is bad (note, paracetamol is acetaminophen):

385px-paracetamol_metabolism-svg1

The toxicity of acetaminophen has been recognized since at least 1966. As I’ve discussed before, acetaminophen poisonings are a significant public health issue. The acetaminophen poisoning antidote is a universal feature of emergency rooms – overdoses are that common. The raw numbers are huge: 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] and acute liver failure, than any other drug product.

Poisoning from acetaminophen will usually take one of two forms:

  • the one-time ingestion of a massive dose (e.g., a suicide attempt)
  • the prolonged ingestion of a dose that exceeds the body’s ability to eliminate the drug safely

Between the two, massive single overdoses are much easier to manage medically. An antidote (acetylcysteine) does exist, which can save an individual’s liver, and their life, if given within 8 hours of an overdose. Poisoning due to chronic ingestion, which are often unintentional, are far more difficult to manage. The early signs of liver damage are not obvious, and can mimic flu-like symptoms. Once hepatic damage has started, the antidote’s effectiveness drops. In severe cases, a liver transplant is required.

It’s the second form of overdose, the inadvertent poisonings, that are understandably the focus of the ProPublica/TAL investigation. Let’s examine the “takeaways” in order. The first is the number of acetaminophen deaths, which they claim at 150 per year in the USA. While The Poison Review disagrees with the show’s methodology and its fatality calculations, the FDA’s own estimate was 458 deaths (from all causes) per year in the period 1990-1998. Case reports collected over the past several decades attest to the fact that unintentional poisonings do occur regularly, although the distinction between deliberate and inadvertent overdoses isn’t always clear, especially when the poisoning is fatal. So while there is some legitimate controversy over the actual numbers, there is no question that accidental poisonings do occur.

TAL/ProPublica’s second “takeaway” is that acetaminophen has a narrow safety margin. Again, it is well established that massive overdoses are fatal unless treated promptly. What is less clear is when liver toxicity becomes an issue with acetaminophen use. The normal maximum dose for adults is 4,000mg per day, and toxicity is felt to be unlikely from a single dose of 7.5-10g. What’s not clear is whether modestly but consistently exceeding the 4,000mg/day maximum is likely to cause harm, or if 4,000mg/day may be too much for some. Case reports suggest that even repeated daily doses of 5,000mg/day to 7,500mg/day have been associated with liver damage. That’s obviously concerning, as modestly exceeding the maximum dose could easily and inadvertently occur from ignoring the dosing instructions, calculating the wrong dosage (particularly in children), or taking two products that both contain acetaminophen.

Acetaminophen is unquestionably toxic in overdose, and potentially harmful at or above the maximum recommended dose. So does that mean that NSAIDs are always preferable? Not necessarily. Massive overdoses of anti-inflammatory drugs are, on balance, less harmful than acetaminophen. Deaths from acute overdose of NSAIDs are rare. What is more insidious and problematic with NSAIDs is the side effect profile I described above. What’s worse, NSAIDS have the potential to cause significant harm, even when dosed appropriately. The Propublica/TAL reports don’t elaborate on the full toxicity profile of the NSAIDs, which implies they are safer – a potentially misleading comparison. Comparing acetaminophen’s toxicity with NSAIDs isn’t an apples-to-apples comparison, and it can’t be quantified. Which is worse in overdose? Acetaminophen. What’s more likely to cause harm at normal doses? NSAIDs. Which is the safest for any given person? It depends. This is the crux of the issue, and I’ll come back to this later. Considering 28 billion doses of acetaminophen were consumed in 2005, this suggests the overwhelming majority of acetaminophen users are not encountering toxicity and poisoning problems with their use.

This isn’t to say that we should accept 150-400+ deaths per year as an acceptable cost of making a drug available, if there are ways we can minimize overdoses, especially the unintentional ones. The third “takeway”, that the FDA has been aware of this issue for years, should not be a surprise. The toxicity of acetaminophen has been understood since the 1960s by health professionals and regulators alike. The population-level harms are well documented in the medical literature. What’s relevant is whether the regulator acted appropriately to address this information. This is the investigation’s fourth takeaway, and where the most effective points in the investigation are made. The FDA has been discussing various measures to enhance various aspects of acetaminophen’s labeling for an astonishing 30 years, with very little to show for it. Recommendations have been drafted, formal advice has been provided, and the FDA has repeatedly deferred making substantive labeling, packaging, or regulatory changes that have the potential to reduce the risk of accidental poisoning. The investigation does a good job describing some of the major changes recommended, and why they are warranted.

The TAL episode describes the tragic death of an infant who died of an overdose due to a dosing error, caused by confusion between different brands of Tylenol liquid. Two formulations for pediatric use have traditionally been available – a concentrated version for infants, dispensed with a dropper, and a less concentrated version for children, dispensed with a spoon or oral syringe. In the case described, the parents were given dosing instructions for Tylenol based on the children’s version of the drug. The parents gave the same volume of the infant formula, resulting in an overdose. The baby suffered liver failure and eventually died of acetaminophen poisoning. This tragic, preventable death sets up TAL and Propublica for a discussion of both manufacturer and regulator behavior, and how the actions (and inactions) of both parties may have been factors in these deaths.

The FDA tightly regulates what drug manufacturers can say about the drugs they sell. Before any manufacturer of over-the-counter drugs can change the dosing instructions on its label, it must obtain FDA approval. And that approval can take years, TAL/Propublica discovered. Unless you’ve ever tried to give Tylenol to an infant, you may not know that Tylenol products sold in the USA do not contain instructions for dosing children under the age of two. The instructions indicate that consultation with a physician is required. There’s no therapeutic reason for this – dosing instructions for this age group are listed on Tylenol bottles sold in Canada, for example. McNeil has been asking the FDA to approve a label change for years, arguing that specific instructions will reduce the likelihood of simply guessing the dose, potentially raising the risk of overdose. The FDA has just recently agreed, and this label change is coming, which should reduce the risk of wrong doses.

One step that McNeil could have done, TAL/Propublica argues, would have been for McNeil to remove one version of its Tylenol liquid, which would eliminate the risk that one product could be accidentally substituted for each other. But McNeil didn’t act. A recent change approved by the FDA will mean the two products will continue to exist – but at the identical concentration, so substitutions won’t carry the same risk. (Interestingly, both products, at two different concentrations, continue to be sold in Canada.) This isn’t the only issue the investigation finds with McNeil. The website includes a much longer list of McNeil’s actions that appear to put business interests ahead of safe use: It has repeatedly fought labeling changes that would put it at a competitive disadvantage to its competitors in the pain reliever marketplace. It fought the FDA’s modest public service campaign to warn about the risks of acetaminophen overdose. And it never disclosed to the FDA its own (ultimately abandoned) work to develop a safer formulation of acetaminophen.

In fairness to McNeil however, it needs to be reiterated that Tylenol is just one brand of acetaminophen liquid among hundreds of acetaminophen products on the market. Without the FDA compelling the entire market to change its labeling or packaging, it’s unlikely that a single manufacturer (albeit the biggest) would act alone. And it’s not clear that different manufacturers, each selling their own concentrations of acetaminophen liquid, would actually create a safer marketplace for consumers. For these types of changes to be truly effective, there needs to be a coordinated approach that applies to all manufacturers – one that only the FDA could have mandated. But it didn’t, for years.

So what are we ultimately left with? Balancing access against patient safety has no single correct answer. There are no risk-free strategies – even shifting use of acetaminophen to substitute drugs, like NSAIDs, could have unforeseen negative consequences. The Propublica/TAL investigation succeeds in raising the toxicity profile of acetaminophen among the public. I hope it will encourage consumers to follow the directions carefully, and to double-check the ingredients and doses of the acetaminophen products they use. It has also shone a bright light on the FDA’s regulatory inertia, which may compel more decisive and timely action to improve labeling, which may in turn reduce accidental overdoses. Where the investigation is weaker is in describing the relative risk of acetaminophen compared with its substitutes, which may leave consumers with the erroneous impression that NSAIDs are safer and more appropriate for pain relief and fever reduction. My personal take is that acetaminophen, when used appropriately, is an exceptionally safe medication, with several substantial advantages over NSAIDs. But I also agree that there’s a lot more that can and should be done to improve the public’s capacity to use this medication safely. Ultimately as a health professional I’m an advocate for appropriate regulation and marketing that gives consumers the information they need to make informed and safe decisions about their own care.

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

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34 thoughts on “Acetaminophen: Still the pain reliever you should trust?

  1. cloudskimmer says:

    How does advanced age affect risk of overdose? Do the elderly run the risk of live damage at lower doses than the maximum specified on the label? Since the elderly suffer more from chronic arthritis pain, and presumably take more acetaminophen than younger persons, are they more likely to suffer liver damage, and does this happen below the maximum dose on the label? I heard some of the show and realize that babies are vulnerable and cute, but the elderly also need help in sorting out this issue.
    How many names are there for Tylenol, and could the FDA mandate a single name for the label of all drugs containing it to avoid confusion and overdose risk? Manufacturers want to protect their brand, of course, but this makes it very confusing for consumers. Very tiny type also reduces the likelihood that consumers will read and understand the labels, and are even more of a problem for the elderly. Have you checked out a medication package insert recently? They are so densely packed with information, and the typeface is so small that they are almost impossible to read. Are they written for consumers or lawyers?
    Thank you for your remarks about the program.

    1. lilady says:

      Liver and kidney function is somewhat impaired (as part of the aging process).

      http://www.editorsweb.org/medications/elderly.htm

      If you (are able to), read the small print on the Physicians Prescribing Information, for some drug classes such as tranquilizers and psychotropic medication, you will see a section for prescribing doses for “the elderly”…usually classified as people age 65 and older. Basically, starting dose is lower than the dosage prescribed for younger adults.

      The generic name for Tylenol is acetaminophen and you will usually find acetaminophen stacked alongside Tylenol on pharmacy shelves.

      Small print? My mail order pharmacy and my local pharmacy always provide me with a printout with single dose and daily dose information, along with other information (take on an empty stomach, take with food, do not take with certain other prescribed or OTC medications, etc,) Dear hubby hasn’t kicked me to the curb…yet…because I am able to read the tiniest print. :-)

      1. MTDoc says:

        Chronic liver disease can be easily overlooked. Anecdote coming up. I once performed an intake evaluation for a heroin addict for an inpatient treatment facility. The referring physician was conned into giving him a Rx for 30 percocet to tide him over and/or as a condition to consider treatment. When I interviewed him, he had obviously taken some of that Rx, but we found out later he had taken them all. Because of his addiction, he had a high tolerance, and the oxycodone hardly affected him at all. But when he failed to show up for admission four days later, I learned that he had died of acute liver failure. The irony is that it was the acetaminophen that killed him, not the opiate. A dose of 10 grams was enough to be fatal in someone who was also a chronic alcoholic. I never could understand why acetaminophen would be put in a compound with such a high risk of abuse. I might have caught this problem in a preventable stage, but I would never have used percocet in the first place, and was not familiar with its composition. Anyway, cirrhosis or any compromise in liver function will most certainly affect ones tolerance to “tylenol”.

        1. Young CC Prof says:

          I always thought that the function of acetaminophen in combination pain relievers WAS as a poison. The combination ones are easier to obtain than the pure ones, after all, and the reason is apparently that mixing in Tylenol reduces the risk of abuse by making the drug rapidly toxic with overdose.

      2. cloudskimmer says:

        Thanks for the information, lilady; I enjoy reading your responses. Unfortunately the acetaminophen I buy is the store brand, and the label contains warnings for kids under 12, but nothing about the elderly. Another complicating factor might be when the person is underweight; surely the dose should be different for a 90 pound person versus a 180 pound person? Or maybe not? And while I can imagine pharmacists printing out large type versions of prescription drugs, I doubt they would be willing to do it for OTC medications. Label information there is very limited anyhow, though they do state 4000 mg as the limiting dose. The only warning for taking it long term is the suggestion to ask your doctor; there are probably no studies in the elderly taking it on a daily basis for years, as is probably done by many elderly people with chronic pain.
        And obviously, the ‘live’ above should be ‘liver.’ Bad proofreading.

  2. Chris Hickie says:

    Infant Tylenol and children’s Tylenol (and their generic counterparts) were, in the US, taken to the same concentration (160 mg/5ml) about 2 years ago, so I am confused as to which lquid Tylenols are existing at different concentrations.

    Also I’ve had two relatives receive “IV Tylenol” while in the hospital in this last year. Both times they were told it was superior to oral Tylenol. I will tell you it sure cost a lot more.

    Thank you for this article. There is a point at which I feel some of these safety advocates are not considering the consequences of removing a drug like acetaminophen from the market–which as you point out would probably drive more use of NSAIDs.

    Nothing in this world is 100% safe.

    1. lilady says:

      Tylenol IV? Apparently, there is a market for it post-op, as adjunct therapy along with opioid analgesia:

      http://www.pharmacytimes.com/publications/health-system-edition/2012/Jan-2012/-IV-Acetaminophen-Ofirmev-

    2. Rebecca says:

      We use IV Tylenol for patients who are unable to absorb enterally – particularly our hem/onc population with graft vs. host of the gut, etc. The cost however is ghastly, which makes other analgesics more attractive unless you are specifically looking for non-narcotic and non-NSAID options.

  3. Carmine says:

    I really enjoyed reading your article and would like to hear any insight you might have on Acetaminophen toxicity and Gilbert Syndrome. Gilbert’s syndrome (GS) is a commonly inherited metabolic condition that affect 5-10% of the population. The glucuronidation pathway of Paracetamol is affected in a subset of GS patients. Because GS is deemed to be benign and inconsequential, rarely do doctors talk with their patients about this possibility. As a person affected by GS, I have never been able to get a straight answer regarding the 4g/day limit and if I should take less. Considering that the incidence of GS is frequent in the general population, should the medical community do more to ascertain that GS patients are not at increased risks of Acetaminophen toxicity and also that a warning be included on packages?
    Thanks.

    1. Angora Rabbit says:

      Seconding what Carmine and MTDoc point out, that a further complication in estimating toxicity is human variance in the alleles and expression of the enzymes that metabolize acetaminophen. As usual, Wiki has a nice summary on this:

      “Production of NAPQI is due primarily to two isoenzymes of cytochrome P450: CYP2E1 and CYP1A2. The P450 gene is highly polymorphic, however, and individual differences in paracetamol toxicity are believed due to a third isoenzyme, CYP2D6. Genetic polymorphisms in CYP2D6 may contribute to significantly different rates of production of NAPQI. Furthermore, individuals can be classified as “extensive”, “ultrarapid”, “intermediate” and “poor” metabolizers (producers of NAPQI), depending on their levels of CYP2D6 expression. Although CYP2D6 metabolises paracetamol into NAPQI to a lesser extent than other P450 enzymes, its activity may contribute to paracetamol toxicity in extensive and ultrarapid metabolisers, and when paracetamol is taken at very large doses.[78] At usual doses, NAPQI is quickly detoxified by conjugation with glutathione.[43][77] Following overdose, and possibly also in extensive and ultrarapid metabolizers, this detoxification pathway becomes saturated, and, as a consequence, NAPQI accumulates causing liver and renal toxicity.[43]”

      What Wiki doesn’t mention is that It’s Cyp2E1 that is induced by regular ethanol use (meaning a social drink/day, or several drinks on the weekend). So individuals with higher 2E1 levels might make more of the problematic NAPQI. If one drinks simultaneously, presumably it sends more into 2D6 pathway (ethanol competition for 2E1). 1A2 is induced aryl hydrocarbons (think dioxin) and not a significant enzyme under most circumstances.

      Above this is allelic variation in the preferred glucuronidation and sulfonation pathways, as Carmine points out. And if the liver is damaged from, say, hepatitis or alcoholism, that is a further complication. All of which makes it challenging to predict with certainty where the toxicity threshold for any individual might be.

      For those who keep track, acetaminophen poisoning was what the scientist used who killed himself over the anthrax letters back in 2001 (am forgetting his name).

  4. Carl says:

    Speaking of dosing errors, don’t forget how sloppy it can get even if you are using the right drug:
    http://www.sciencebasedmedicine.org/good-idea-bad-execution-dosing-errors-a-preventable-harm/

    (still disappointed that the alligator spoon was not tested)

    1. Calli Arcale says:

      I remember being quite happy when my little ones got old enough to take chewable Tylenol; you get a much tidier, discrete dose that way. Not that I ever had difficulty filling cups properly, thanks to both chemistry lab and plenty of measuring in the kitchen to make me familiar with both how to properly use a liquid measure, and also how to convert between metric and US kitchen measures. But it was still rather a relief to be able to just to give her one or two tablets. Also, much less messy. Dang, that stuff’s sticky.

  5. Andrew L says:

    I use Iv acetaminophen very often in the management of acute and post operative pain. In various studies it reduces opioid consumption by about 30% which is also similar to the amount reduced by Iv NSAIDs (toradol). The great advantage to Iv acetaminophen is that it can be given to abdominal surgery cases that are usually unable to take medicine orally for a day or two post op. by reducing narcotic consumption you also theoretically allow the bowels to recover quicker as narcotic agents tend to exacerbate post op illeus (slow the bowel function). It also works better because the necessary blood level and csf levels (where acetaminophen is theorized to have its analgesic effect) is higher because it avoids first pass metabolism by the liver (this occurs with orally taken medications). A higher dose of acetaminophen is generally needed to achieve analgesia than is required to reduce fever.

    1. Chris Hickie says:

      Do you still get the same first pass metabolism for PR tylenol? I was present with one relative when the IV tylenol was given, and no narcotic medication was required (which was nice), but it wasn’t covered by the insurance and the cost was a few hundred bucks (as per hospital charges), which was, to me a lot of cost for that one dose.

      1. Chris Hickie says:

        From a Medscape article: (http://www.medscape.com/viewarticle/764841_4). Interesting stuff. Also interesting its trade name is Ofirmev, is 1000 mg in a 100 ml IV bottle and wholesales at ~$13/bottle, which means I got billed at about 30 times its cost by the hospital, which is ridiculous.
        ————–

        IV Acetaminophen

        Intravenous acetaminophen differs in many ways from the available IV opioids and NSAIDs. It is the only approved IV nonopioid analgesic that does not include a boxed warning on the label and that is indicated for use in pediatric patients. The drug is not associated with the increased incidence of nausea, vomiting, and respiratory depression that can occur with opioids, or the platelet dysfunction, gastritis, and renal toxicity that are sometimes associated with NSAIDs (Haas, 2002; Silvanto, Munsterhjelm, Savolainen, Tiainen, Niemi, Ylikorkala, … Olkkola, 2007).

        Intravenous acetaminophen has a faster onset and results in more predictable pharmacokinetics than oral or rectal acetaminophen formulations (Bertolini et al., 2006, Malaise et al., 2007). In a recent study, in which six adult volunteers were given IV, oral, or rectal acetaminophen, the mean IV Cmax (maximum plasma concentration of drug) was nearly twice that observed with oral administration and nearly four times that observed with rectal administration (Singla, Parulan, Samson, Hutchinson, Bushnell, Beja, & Royal, 2011). The IV group showed consistently earlier and higher peak plasma and cerebrospinal fluid (CSF) maximum concentration values than after either oral or rectal delivery. The variability in plasma and CSF results was much higher in the oral and rectal groups than in the group that received IV acetaminophen.

        A major benefit is that IV acetaminophen may be administered before or during surgery, permitting the initiation of effective analgesic therapy in the early phase of the postoperative period (Dahl & Møiniche, 2004; Ong, Lirk, Seymour, & Jenkins, 2005). When patients are able to tolerate oral intake, they may be switched from IV to oral acetaminophen to maintain the predictable analgesia established by the IV route (Pergolizzi, Raffa, Tallarida, Taylor, & Labhsetwar, 2011).

        Intravenous acetaminophen appears to avoid first-pass hepatic exposure and metabolism via portal circulation, which may reduce the potential for hepatic injury (Jahr & Lee, 2010). With therapeutic dosing (up to 4,000 mg daily) (Gregoire, Hovsepian, Gualano, Evene, Dufour, & Gendron, 2007), IV acetaminophen is rarely associated with hepatotoxicity, and it has been shown to be safe for use in some patients with underlying liver conditions (Benson, Koff, & Tolman, 2005; Rumack, 2002). Nonetheless, according to its prescribing information, IV acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease (Cadence, 2010).

        Because of its efficacy, safety, lack of clinically significant drug interactions, and lack of the adverse effects associated with other analgesics, IV acetaminophen is an attractive component of a multimodal analgesic treatment plan (Groudine & Fossum, 2011).

  6. Andrew L says:

    Btw, this is from memory when I first started using Iv Tylenol about two years ago. I would need to hunt down the references but am unable to currently while on a relatively busy call tonite.

  7. Yodeladyhoo says:

    My pet peeve is that most people don’t seem to know that taking acetominophen along with drinking can be harmful. I just checked the label on my bottle of generic acetopminophen – it says, “Severe liver damage may occur if… adult has 3 or more alcoholic drinks every day while using this product.” Is it safe if we only have two drinks on Sundays?

    Seriously — how dangerous is it when mixed with alcohol?

    Aspirin was a terrific little pain reliever. I miss it.

    1. Calli Arcale says:

      I seem to recall reading that it is only if you are a *chronic* drinker (i.e. you routinely drink enough to get drunk) that the danger arises. If you are only an occasional drinker or seldom go above 1 drink a day, then you have not activated the other metabolic pathway.

    2. Calli Arcale says:

      BTW, aspirin is still very much available where I live, in Minnesota, both alone and in combination drugs. Excedrin, for instance, is a combination of aspirin, acetominophen, and caffeine.

  8. Stephen H says:

    FUD: it pays (some) journalists’ salaries.

    A mentally ill man died in my city (population around 250,000) several years ago, after drinking too much water. I have yet to see warning labels on bottles of water and water dispensing products such as taps and drinking fountains.

    Take a high enough dose and everything turns out to be a poison.

    1. Charon says:

      While people do very occasionally die of hyponatremia, nobody dies from drinking one more glass of water than normal. One of the major concerns about acetaminophen, as Scott pointed out, is that the effective dose is so close to a harmful dose. And many people believe “OTC, so can’t be that harmful”.

      The solution to going too far in one direction (which ProPublica may have done) is not to go much farther in the other direction (as you’ve done), but to give a clear and well-supported argument. As SBM did (as usual).

    2. hat_eater says:

      Take a high enough dose and everything turns out to be a poison.

      Unlike water, “(t)he safety margin (safe dose vs. toxic dose) with acetaminophen is small”.
      And with diminished liver function this margin seems to be creeping into previously safe territory (“63 percent of those in the accidental-overdose group and 25 percent of those in the suicidal group were chronic alcohol abusers (P = 0.009)”).

  9. Jeff says:

    As Scott notes, n-acetylcysteine (either oral or infused) is an FDA-approved antidote for acetaminophen toxicity. Since NAC is a safe, inexpensive dietary supplement, why not include some with every dose of Tylenol?

    http://www.lef.org/magazine/mag2010/may2010_N-Acetyl-Cysteine_01.htm

    1. DugganSC says:

      Heh, according to the link you provided, apparently they already do, although the article states it as a “co-opting” tactic by the drug companies.

      And acetylcysteine is approved by the FDA as an antidote, not for general prophylactic use. Doing a quick peek around the web, more frequent use of it has been correlated with heart and lung problems, and use of it after drinking can cause liver damage (although, if taken before, it may help).

  10. Jeff says:

    As Scott notes, n-acetyl cysteine (either oral or infused) is an FDA-approved antidote to acetaminophen toxicity. Since NAC is a safe, inexpensive compound, why not include some with every dose of Tylenol?

    http://www.lef.org/magazine/mag2010/may2010_N-Acetyl-Cysteine_01.htm

  11. Scottynuke says:

    Color me shocked, shocked I tell you, to hear ProPublica oversells the dangers and the “corporate/government malfeasance” angle.

    Can more be done to improve effective labeling for acetaminophen? Of course, but to trot out “150 deaths a year” or “1,500 deaths in the past decade” without the overall risk equation (I saw no reference to the yearly estimate of doses given in a quick review of the main article) is irresponsible journalism at best, and more likely fearmongering “click bait.”

  12. Jon says:

    I learned this last year when a friend started to get bloated and discovered it was a side effect from taking higher than usual doses of acetaminophen. Most people view it as harmless which can be quite misleading. Some also take it when drinking alcohol, which can lead to liver damage.

  13. oldebabe says:

    What about Vicodin (50% acetaminophen), or Norco (30%)? Especially for the elderly who like red wine (dare I say old people like me?) and who also feel back pain? Or I guess we’re now just a minority…

    A bell curve representation does not represent every situation, if you know what I mean.

    1. lilady says:

      The FDA has requested that the manufacturers of Vicodin (and generics), reduce the amount of acetaminophen to 325 mg. per dose, to decrease the risk of liver toxicity.

      http://www.uspharmacist.com/email/ECF1229.html

  14. oldladyirene says:

    Wow! I’m a little late on this one–missed it somehow. I have only taken acetaminophen once or twice, a long time ago. When I have a procedure I request my codeine with aspirin and I eventually get it. This is all because it just doesn’t work for me (or so I felt 30 years ago), but now I’m very glad of it. o_o

  15. MrAptronym says:

    I take Acetaminophen whenever I have pain issues, as my medication has interactions with NSAIDs. I have always been careful on dosing; I read up on potential problems from any drug I take. Its nice to read here about the actual biological mechanisms at work.

    I never knew just how close a dangerous dose is to an effective treatment dose though. I never take more than half the recommended daily maximum, as I tend to only need it for short term heachaches and other aches, but I wonder how much the safe maximums vary person to person.

  16. skipbidder says:

    ProPublica is simply not a reliable voice on medical issues.
    Instead they are a sensationalist one.
    (This makes me reluctant to trust anything they say on other issues, despite my views generally being politically congruent.)

    Interesting to me, given their unbalanced stories overstating the dangers of opioids, that they are also overstating the risks of the single most useful analgesic that I can recommend prior to (or instead of) opioids.

  17. Simon fff says:

    I’m surprised nobody has yet talked about the legislation that was introduced in the UK, simply limiting the package size.
    While the number of overdoses remained largely unchanged the number of accidental deaths seems to have been greatly reduced.
    http://www.bmj.com/content/346/bmj.f403
    Obviously this may not be applicable o other markets where package sizes and dosages may be different.

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