Stop the pain!!!!

Some time ago, Savage and I had a talk in which the concept of pain came up. I won't go into the details of the conversation but I will say that at the end we both sort of agreed that pain is a very important issue in human life. I don't think there are many people out there who like pain. And once you start thinking about pain, you start thinking about pain killers (e.g. acetaminophen, ibuprofen, acetylsalicylic acid). Many people are also sort of used to having these pills at hand, after all they are sold over the counter (OTC), but I have a feeling that just a very little number of them actually know how they work. This post is about that, about how they stop the pain.

OTC pain killers fall into a category called Non-Steroidal Anti-Inflammatory Drugs or NSAIDs. Acetaminophen (better known as Tylenol) is usually (and unofficially) considered in this category even though it is not really an anti-inflammatory drug. The main reason is that although it doesn't prevent inflammation, the mechanism of action is somewhat similar to that of ibuprofen (Advil, Motrin) or acetylsalicylic acid (aspirin), or at least that's the assumption. We'll talk about this later and you'll see how little it's known about acetaminophen.

So what is this mechanism? It is the inhibition of a class of enzymes called cyclooxygenase (COX for short). The COX enzymes are involved in the production of prostaglandin and thromboxane. Prostaglandin is the carrier of the message of damage (and the body's reaction is to let you know by creating pain) while thromboxane is involved in clot formation. So, by blocking the COX enzymes, the pain killers make it difficult for the body to know it's hurt and also prevent blood from clotting (this is why in many cases doctors cannot operate on you if you are taking aspirin until your body is free of it).

You can get into more detail and notice that there are several COX enzymes: COX-1, COX-2 and COX-3 and as you can imagine they have different roles. COX-1 is actually a regulator of many physiological processes and serves as a protector of the stomach lining. COX-2 is the one that raises the levels of prostaglandin when there is inflammation of tissue. This is the one that when blocked, produces the wanted effects of pain killers. COX-3 has just recently been discovered and the role is still unknown. Since NSAIDs block COX-1 too, you can now see why ibuprofen or aspirin can cause stomach ulcers, you are basically left without the protective element when you take those pills. Some attempts have been made at developing an specific COX-2 inhibitor and leaving the other ones unaffected but the results have been at least highly controversial, aside from the fact that lab tests show that although specific to COX-2 inhibition these drugs still cause stomach lining damage, the side effects of these new drugs seem to be very serious (think Celebrex or Vioxx).

Ibuprofen blocks both COX-1 and COX-2, while aspirin seems to have a larger effect on COX-1 than COX-2. That is why aspiring "thins" out the blood more than the others. What about acetaminophen?

Well, remember that at the beginning I said acetaminophen was considered an NSAID even though it didn't prevent inflammation? This in turn would indicate that it doesn't block COX-2 and since it doesn't affect blood clotting much then it should mean that COX-1 is also unaffected to a good extend by acetaminophen. So, why is it thrown together with NSAIDs and what the hell does it do to make pain go away? The reason it is put together with NSAIDs is because it seems that acetaminophen also blocks COX enzymes but the real mechanism of action is still debated. Some people argue it is actually COX-3 that is being blocked but the explanations as to how acetaminophen blocks pain without reducing inflammation are still speculative at best. For example, one idea is that acetaminophen cannot do its job in an environment where there is inflammation. This implies that acetaminophen actually in the central nervous system which seems to fit the observed effects. The bottom line is that very little is known about the most popular OTC pain medication.

Also, remember that while pain is awful and one would like to avoid it, overdosing (even just a single time) on NSAIDs or acetaminophen can cause acute liver damage. The chances of surviving this are rather slim so be conscious when consuming these medicines. Just because they work and are sold without much hassle doesn't mean that we understand them well nor that they come with no side effects.