The Mystery in the Medicine Cabinet

Dynomight Acetaminophen, ibuprofen, and what doctors probably want you to know. Lots of people die after overdosing on acetaminophen (paracetamol, often sold as Tylenol or Panadol). In the U.S., it’s estimated to cause 56,000 emergency department visits, 2,600 hospitalizations, and 500 deaths per year. Acetaminophen has a scarily narrow therapeutic window. The instructions on the package say it's okay to take up to four grams per day. If you take eight grams, your liver could fail and you could die. Meanwhile, it seems to be really hard to kill yourself by overdosing on ibuprofen (Advil, Nurofen, Motrin, Brufen). In 2006, Wood et al. searched the medical literature and found 10 documented cases in history. Nine of those cases involved complicating factors, and in the 10th, a woman took the equivalent of more than 500 standard (200mg) pills. So, for many years, if I needed a painkiller, I’d try to take ibuprofen rather than acetaminophen. My logic was that if eight grams of acetaminophen could kill my liver, then one gram was probably still hard on it. I’m fond of my liver and didn't want to cause it any unnecessary inconvenience. But guess what? My logic was wrong and what I was doing was stupid. I’m now convinced that for most people in most circumstances, acetaminophen is safer than ibuprofen, provided you use it as directed. I think most doctors agree with this. In fact, I think many doctors think it’s obvious. (Source: I asked some doctors; they said it was obvious.) Should this have been obvious to me? I figured it out by obsessively researching how those drugs work and making up a story about metabolic pathways and blood flow, and amino acid reserves. It’s a good story, one that revealed that my logic stemmed from an egregious lack of respect for biology and that I’m a big dummy (always a favorite subject).

But if the clearest road to some piece of knowledge runs through metabolic pathways, then I don't think that knowledge counts as obvious. So how is a normal person meant to figure it out? Why doesn't the fact that acetaminophen is typically safer than ibuprofen appear on drug labels or government websites or WebMD? Are normal people supposed to figure it out, or has society decided that this is the kind of thing best left illegible? Note: You should not switch medications based on the uninformed ramblings of non-trustworthy pseudonymous internet people.

Jul Quanouai How does ibuprofen work?Ibuprofen inhibits the body’s production of the Cyclooxygenase (COX) enzyme. This in turn inhibits the formation of messenger molecules involved in inflammation, which leads to less physical inflammation and thus less pain. The same story is true for almost all over-the-counter painkillers, which is why they’re almost all considered “non-steroidal anti-inflammatory drugs,” or NSAIDs. This includes ibuprofen, aspirin, naproxen (Aleve), and a long list of related drugs. But it does not include acetaminophen.How does acetaminophen work?Nobody knows!Like ibuprofen, acetaminophen inhibits some COX enzymes. But it does so in a weird way that barely affects inflammation or messenger molecules, so it’s unclear if this matters for pain reduction. In the brain,  acetaminophen is metabolized into a mysterious chemical called AM404. This activates the cannabinoid receptors and increases endocannabinoid signaling, which seems to reduce the subjective experience of pain. AM404 also activates the capsaicin receptor, which is associated with burning sensations that you’d normally expect to increase pain, but maybe some desensitization thing happens downstream? And maybe acetaminophen also interacts with serotonin or nitric oxide or does other stuff? How this all comes together to reduce pain is still somewhat a scientific mystery. Aside: When trying to understand painkillers, it’s natural to focus on chemistry and molecular biology. But the unknown physical origins of consciousness are always nearby, looming ominously.

What risks does ibuprofen have?In an ideal world, the only thing ibuprofen would do is reduce inflammation in the part of your body that hurts. But that is not our world. When ibuprofen inhibits the COX enzymes, it does so throughout the body. And mostly, that is bad. For one, ibuprofen reduces production of mucus in the stomach. That might sound okay or even good. But stomach mucus is important. You need it to shield the lining of your stomach from your extremely acidic gastric juice.1 Having less mucus can lead to gastrointestinal problems or even ulcers. Ibuprofen also affects the heart. When ibuprofen inhibits the COX enzymes there, this in turn inhibits one chemical that prevents clotting and another that causes clotting. In balance, this seems to lead to more clotting, and an increased statistical risk of heart attacks 2 . If you’re healthy, the risk of a heart attack from an occasional low dose of ibuprofen is probably zero. But if you have heart issues and take medium to large doses regularly for as little as a few days, this might  be a serious concern. Ibuprofen also affects the kidneys. If you’re stressed, or cold, or dehydrated, or take stimulants, your body will constrict your blood vessels. That squeezes your kidneys’ intake tube, depriving them of blood. Your kidneys don’t like that, so they release signaling molecules to locally re-dilate the blood vessels. Trouble is, when ibuprofen inhibits COX enzymes in the kidneys, it inhibits those signaling molecules. If everything is normal, that’s okay, because the kidneys wouldn’t try to use those molecules anyway. But if your body has clamped down on the blood vessels, then the kidneys don’t have the tool they use to keep blood flowing, meaning they don’t get as much blood as they want. This is bad.3 There are many other less common side effects, including allergies, respiratory reactions in asthmatics, induced meningitis, and suppressed ovulation. If you take a lot of ibuprofen, this could hurt your liver. But the major concerns seem to be the stomach, the heart, and the kidneys.What risks does acetaminophen have?Acetaminophen also inhibits some COX enzymes.

But unlike ibuprofen, the effect is minimal outside the central nervous system. Thus, acetaminophen has little effect on stomach mucus, blood clots, or blood flow, and so presents almost none of the risks that ibuprofen does. Even so, if you take too much acetaminophen at once, you could easily die. How does this happen? Well, when acetaminophen is metabolized by the liver, it’s mostly broken down into harmless stuff. But a small fraction (5-15%) is broken down by the P450 system into an extremely toxic chemical called NAPQI. Ordinarily this is fine; your body creates and neutralizes toxic stuff all the time. For example, if you drank 20 grams of formaldehyde, you’d likely die. But did you know that your body itself makes and processes ~50 grams of formaldehyde every day? When liver cells sense NAPQI, they immediately release glutathione, which binds to NAPQI and renders it harmless. But there’s a problem. If you take too much acetaminophen at once, the pathways that break it down into harmless stuff get saturated, but the P450 system doesn’t get saturated. This means that not only is there more acetaminophen, but also that a much larger fraction of it is broken down into NAPQI. Soon your liver cells will run out of glutathione to neutralize it. Then, NAPQI will build up and bind to various proteins in the liver cells (especially in mitochondria) causing them to malfunction and/or commit suicide. This can cause total liver failure. So you should never take more than the recommended dose of  acetaminophen.4 If you do take too much, you should go to a hospital immediately. They will give you NAC, which will replenish your glutathione and neutralize the NAPQI. Your prospects are good as long as you get to the hospital within a few hours. 5 6 Acetaminophen has lots of other possible side effects, like skin issues and blood disorders. But these all seem to be quite rare.What if you have liver issues?The primary concern with acetaminophen  is liver damage. So if you have liver disease, then surely you’d want to avoid acetaminophen and take ibuprofen instead, right?

Nope. It’s the opposite. Liver disease shifts the balance of risk in favor of acetaminophen. With liver disease, it’s hard for blood to flow into the liver, meaning that blood tends to pool in the abdomen. To counter this, blood vessels elsewhere in the body contract. This includes blood vessels around the kidneys. Remember the kidneys? Again, when blood vessels are constricted, the kidneys send out signaling molecules to locally re-dilate the blood vessels. But those signaling molecules are blocked by ibuprofen. So if you have liver disease, taking ibuprofen risks starving your kidneys of blood just like if you were dehydrated.Meanwhile, people with moderate liver disease are usually still able to process acetaminophen without issue, as long as it’s in smaller amounts. So doctors usually tell patients with liver disease to avoid ibuprofen and take  acetaminophen instead, just with a maximum of two grams per day instead of four. (Obviously, if you have liver disease, then you should talk to a doctor, I beg you, for the love of god.)What about other situations?The main takeaway from all this is that the risks of both drugs emerge from the madhouse of complexity that is your body. Surely there are some situations where acetaminophen is more dangerous than ibuprofen?I tried to capture the most common situations in this table:

It’s actually fairly hard to find situations where ibuprofen is safer than acetaminophen. Possibly this is true if you’re hungover, but I would be very careful, because you tend to be dehydrated when hungover, raising the risk of kidney damage. (It’s probably optimal, from a health perspective, to avoid taking recreational drugs at doses that leave you physically ill the next day.) Aside from hangovers, the only situations I could find where ibuprofen might be safer than acetaminophen  are if you’re taking certain anti-seizure or tuberculosis drugs or maybe if you have a certain enzyme deficiency (G6PDD). So...What have we learned so far? 1. The body is really complicated! 2. The main risk of acetaminophen is liver damage by creating too much NAPQI. Taking too much at once can easily kill you.