Reading this I could not help but think of compliance and treatment safety for self-managed dosing.
It's evident, for example, that drugs such as Paracetamol (Tylenol for you Americans) should be dosed by body weight in children. To make life simpler for parents, they are given age and/or weight brackets, sometimes along with upper thresholds (e.g. mg/day).
This of course means that lighter children are comparatively over-dosed and heavier children under-dosed compared to a median.
The problem is - I think this works pretty well as a safeguard against dangerous over-dosing (i.e. liver toxicity etc.).
Now how would we turn that advice into a gradual dosing recommendation? We can use mg/kg body weight as is done e.g. in antibiotics. But that carries the potentially fatal risk of miscalculation, and some parents might intentionally overdose over a wrong risk perception.
What we would need is something like an exponential risk curve, indicating a "safe zone" and a "danger zone" while highlighting some critical threshold. This again would need to be age/weight-specific.
Do we think parents would be deterred from giving a kid too high of a paracetamol dose? I'm not so sure, especially over time.
So in the end, I think that in some cases (especially with self-administered dosing) round numbers and sharp thresholds may work well to mitigate fatal risks, even while increasing nonfatal risks.
First, many people are ... let's politely call it arithmetically challenged. They won't understand how to compute the amount and then obtain the correct dose. A chart or a table might have more success than a formula, no matter how simple the formula.
Then again, the dangers of paracetamol overdose aren't high (and I would think it's less for children than for adults). It's typically only needed for a few days. Perhaps that's where the stress should go: stop as soon as you can.
Right, the 4g/day number is the amount that should be safe for any relatively healthy adult (minus whatever is making them take the medicine). I should hope it isn't too close to the number where you can cause permanent damage.
It's become fashionable to fearmonger about it lately, but I agree, it's safe to assume the makers wouldn't tolerate the liability that would come with a single extra dose above the given instructions causing that kind of harm.
Yeah I’ve noticed that a lot of cold/flu remedies that have potential for drug abuse have huge amounts of acetaminophen adddes such that if you took both the flu medication and some tylenol, or you took multiple medications you’d be risking killing your liver. I worry that this is intentional.
> Paracetamol is the most common cause of liver failure in the US.
This is also a bit misleading, it’s the most common cause of acute liver failure which is overall quite rare in developed countries. The most common need for transplants are still by far progressive chronic liver diseases leading to cirrhosis.
Depending on location doctors will frequently come into contact with people who are illiterate, as in unable to write down their own names on a piece of paper. They still need care and it cannot wait until society has been fixed.
What you are implying would work great in a world that had prioritized education. We don’t live in that world in America for sure unfortunately.
> The statement is a popular anecdote from the 1980s, illustrating a widespread misunderstanding where many consumers thought that a 1/4 pound burger was larger than a 1/3 pound burger because the number "4" is larger than "3". This led to the failure of a new third-pound burger campaign by the fast-food chain A&W.
Sure, most of us stay in system 1 (heuristic) most of the time.
But I think it's wrong to assume most people are incapable of serious, thorough thinking. Parents around the world correctly dose medication for their kids all the time, and they mostly do this completely fine.
The key is that people are clever when they both can and want to, and some communication regarding drugs is not well-designed to alert them to want at the right time.
https://www.awrestaurants.com/press/press-release/101921-aw-... ("In the 1980s, A&W tried to compete with the immensely popular McDonald’s Quarter Pounder by offering a bigger, juicier ⅓ Pound Burger at the same price. Unfortunately, Americans aren’t so great at math. Confused consumers wrongly assumed that ¼ was bigger than ⅓ (You know, because 4 is bigger than 3) and the whole experiment went down in history as a huge marketing fail.").
Let's suppose arithmetic is a solved problem and only consider manufacturing and distribution.
The major barrier to self-managed dosing, even if you want to do it properly, is that there's a huge difference between one pill and two pills. And trying to cut pills in half (if even possible for a particular pill structure) often makes very uneven halves (which is a problem for day-to-day variation even if a consistent "10% more than half" dose would be fine).
I have seen dose differences of ~10% to be ignored between brands or over time, so that's probably safe-ish to ignore (certainly much better than the current 50%-if-lucky-else-100%). But counting out 10 pills is certainly a pain; realistically, aiming for a 5-pill typical dose would be more reasonable.
My impression from looking at OTC costs is that the bottle costs more than anything, so manufacturing probably isn't the bottleneck. A side-effect of the current "one pill" mindset, in conjunction with expiration dates, is that low-dose pills are generally not available in higher counts, but there's nothing fundamental about this.
Are there any "delayed/gradual release" concerns that get worse for many small pills rather than one large one? If so, is it really more significant than the wrong-dose problem?
Acetaminophen/Tylenol/Paracetamol and many similar drugs are indeed dosed by weight in the hospital but as sibling comments say, this is likely too complex for parents.
In the hospital, a formulary likely carries pills of different medication amounts, so a nurse can readily administer the correct dose - which a parent would struggle with.
> paradoxical risk, where successful treatments unexpectedly lower the risk of higher-risk patients to below that of untreated lower-risk patients.
This seems perhaps tautological whenever the treatment intensity is binary, and it's an effective treatment. Someone at the threshold that receives treatment would necessarily do better than someone at the threshold not receiving the treatment.
It's a pretty good argument against any binary treatments, or at least to set the threshold low enough that improvement with treatment at the threshold is minimal.
This is an amazing paper (but I’m not a statistician, apologies if I am overstating its value).
Note that the GitHub repository associated with the paper is 2 years old and that this journal is not very popular - it likely was sent to Nature or NEJM and not accepted, though I wonder why it wasn’t sent to Health Services Research.
Reading this I could not help but think of compliance and treatment safety for self-managed dosing.
It's evident, for example, that drugs such as Paracetamol (Tylenol for you Americans) should be dosed by body weight in children. To make life simpler for parents, they are given age and/or weight brackets, sometimes along with upper thresholds (e.g. mg/day).
This of course means that lighter children are comparatively over-dosed and heavier children under-dosed compared to a median.
The problem is - I think this works pretty well as a safeguard against dangerous over-dosing (i.e. liver toxicity etc.).
Now how would we turn that advice into a gradual dosing recommendation? We can use mg/kg body weight as is done e.g. in antibiotics. But that carries the potentially fatal risk of miscalculation, and some parents might intentionally overdose over a wrong risk perception.
What we would need is something like an exponential risk curve, indicating a "safe zone" and a "danger zone" while highlighting some critical threshold. This again would need to be age/weight-specific.
Do we think parents would be deterred from giving a kid too high of a paracetamol dose? I'm not so sure, especially over time.
So in the end, I think that in some cases (especially with self-administered dosing) round numbers and sharp thresholds may work well to mitigate fatal risks, even while increasing nonfatal risks.
First, many people are ... let's politely call it arithmetically challenged. They won't understand how to compute the amount and then obtain the correct dose. A chart or a table might have more success than a formula, no matter how simple the formula.
Then again, the dangers of paracetamol overdose aren't high (and I would think it's less for children than for adults). It's typically only needed for a few days. Perhaps that's where the stress should go: stop as soon as you can.
Paracetamol is the most common cause of liver failure in the US. Its toxicity threshold is somewhere around 4g/day for an adult.
I remember that my wife once bought an over the counter cold drug in Italy that had > 1g per pill.
So we should be aware that it's very easy to overdose this particular drug.
More info: https://www.ncbi.nlm.nih.gov/books/NBK441917/
> Its toxicity threshold is somewhere around 4g/day for an adult.
I was surprised it was that low, but I think you misread/misremembered. From your link:
> Toxicity is likely to develop in adults at:
>12 g over a 24 hours, or 7.5 to 10 g in a single dose, or Doses 350mg/kg
The 4g/day is the dosage threshold, but it seems they set it to 1/3 of the toxicity threshold.
Right, the 4g/day number is the amount that should be safe for any relatively healthy adult (minus whatever is making them take the medicine). I should hope it isn't too close to the number where you can cause permanent damage.
It's become fashionable to fearmonger about it lately, but I agree, it's safe to assume the makers wouldn't tolerate the liability that would come with a single extra dose above the given instructions causing that kind of harm.
Yeah, toxic at 2.5x therapeutic level. Crazy in an OTC.
Yeah I’ve noticed that a lot of cold/flu remedies that have potential for drug abuse have huge amounts of acetaminophen adddes such that if you took both the flu medication and some tylenol, or you took multiple medications you’d be risking killing your liver. I worry that this is intentional.
> Paracetamol is the most common cause of liver failure in the US.
This is also a bit misleading, it’s the most common cause of acute liver failure which is overall quite rare in developed countries. The most common need for transplants are still by far progressive chronic liver diseases leading to cirrhosis.
Depends what you call "high", but the risks are far higher than most other drugs relative to availability.
"Paracetamol toxicity is one of the most common causes of poisoning worldwide." -- https://en.wikipedia.org/wiki/Paracetamol_poisoning#Epidemio...
I was once told by a doctor that if aspirin or paracetamol were invented today they probably wouldn't be approved, let alone sold over the counter.
A simple google search resolves this issue:
https://www.tylenol.com/safety-dosing/dosage-for-children-in...
If people aren’t capable of finding this information, or even calculating it, it’s an education system/societal problem.
Depending on location doctors will frequently come into contact with people who are illiterate, as in unable to write down their own names on a piece of paper. They still need care and it cannot wait until society has been fixed.
Oh, then let’s just fix that then! Simple!
What you are implying would work great in a world that had prioritized education. We don’t live in that world in America for sure unfortunately.
> The statement is a popular anecdote from the 1980s, illustrating a widespread misunderstanding where many consumers thought that a 1/4 pound burger was larger than a 1/3 pound burger because the number "4" is larger than "3". This led to the failure of a new third-pound burger campaign by the fast-food chain A&W.
You’re severely overestimating the mental capacity of a large section of the population.
In fact, almost the entire population after little sleep or on a bad day is likely to make mistakes while following your proposed scheme.
Sure, most of us stay in system 1 (heuristic) most of the time.
But I think it's wrong to assume most people are incapable of serious, thorough thinking. Parents around the world correctly dose medication for their kids all the time, and they mostly do this completely fine.
The key is that people are clever when they both can and want to, and some communication regarding drugs is not well-designed to alert them to want at the right time.
> But I think it's wrong to assume most people are incapable of serious, thorough thinking
I never said otherwise. I said that many are incapable, not most
Furthermore it's incredibly convenient to mentally cache volumes like "10mL for this one, 24mL for that one" for ~6-12 months at a time.
https://www.awrestaurants.com/press/press-release/101921-aw-... ("In the 1980s, A&W tried to compete with the immensely popular McDonald’s Quarter Pounder by offering a bigger, juicier ⅓ Pound Burger at the same price. Unfortunately, Americans aren’t so great at math. Confused consumers wrongly assumed that ¼ was bigger than ⅓ (You know, because 4 is bigger than 3) and the whole experiment went down in history as a huge marketing fail.").
Let's suppose arithmetic is a solved problem and only consider manufacturing and distribution.
The major barrier to self-managed dosing, even if you want to do it properly, is that there's a huge difference between one pill and two pills. And trying to cut pills in half (if even possible for a particular pill structure) often makes very uneven halves (which is a problem for day-to-day variation even if a consistent "10% more than half" dose would be fine).
I have seen dose differences of ~10% to be ignored between brands or over time, so that's probably safe-ish to ignore (certainly much better than the current 50%-if-lucky-else-100%). But counting out 10 pills is certainly a pain; realistically, aiming for a 5-pill typical dose would be more reasonable.
My impression from looking at OTC costs is that the bottle costs more than anything, so manufacturing probably isn't the bottleneck. A side-effect of the current "one pill" mindset, in conjunction with expiration dates, is that low-dose pills are generally not available in higher counts, but there's nothing fundamental about this.
Are there any "delayed/gradual release" concerns that get worse for many small pills rather than one large one? If so, is it really more significant than the wrong-dose problem?
Acetaminophen/Tylenol/Paracetamol and many similar drugs are indeed dosed by weight in the hospital but as sibling comments say, this is likely too complex for parents.
In the hospital, a formulary likely carries pills of different medication amounts, so a nurse can readily administer the correct dose - which a parent would struggle with.
> To make life simpler for parents, they are given age and/or weight brackets, sometimes along with upper thresholds (e.g. mg/day).
In my country doctors calculate the exact dosages and write them down on the prescription.
interestingly enough the antidote to tylenol poisoning is ACC (Acetylcysteine), a drug many could have in their household
the acronym is NAC for N-Acetyl-L-Cystenine (the L is implied). With ACC you could theoretically have S-acetyl-L-Cystenine and that not the antidote !
> paradoxical risk, where successful treatments unexpectedly lower the risk of higher-risk patients to below that of untreated lower-risk patients.
This seems perhaps tautological whenever the treatment intensity is binary, and it's an effective treatment. Someone at the threshold that receives treatment would necessarily do better than someone at the threshold not receiving the treatment.
It's a pretty good argument against any binary treatments, or at least to set the threshold low enough that improvement with treatment at the threshold is minimal.
I have heard people gain weight intentionally to ensure they get these new weightloss drugs.
If you're close to the BMI cutoff for it, it makes sense.
This is an amazing paper (but I’m not a statistician, apologies if I am overstating its value).
Note that the GitHub repository associated with the paper is 2 years old and that this journal is not very popular - it likely was sent to Nature or NEJM and not accepted, though I wonder why it wasn’t sent to Health Services Research.
Here is the lab page of the author whose GitHub was used: https://adaptinfer.org/
This is helpful in any number of fields with metrics-driven responses.