How do painkillers work?

[This is a transcript of the video embedded below. Some of the explanations may not make sense without the animations in the video.]

Have you ever taken an Aspirin? Advil? Paracetamol, or Tylenol for the Americans. Most of you probably have. But do you know what’s the difference between them? What’s pain to begin with, where does it come from, how do painkillers work, and why is Sabine suddenly talking about pharmacology? That’s what we’ll talk about today.

Pain is incredibly common. According to a 2019 survey in the United States, almost 60 percent of adults had experienced physical pain in the three months prior to the survey. I’d have guessed that stubbing your toe was the most frequent one, but it’s actually back pain with 39 percent. The numbers in the European Union are similar. The healthcare costs for chronic pain disorders in the European Union alone have been estimated to exceed 400 billion dollars annually. Pain is such a universal problem that the United Nations say access to pain management is a human right.

But just what do we mean by pain? The International Association for the Study of Pain defines it as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.” You probably don’t have to be told it’s unpleasant. But this definition tells you that the “unpleasant experience that accompanies tissue damage” is not always caused by actual tissue damage. We’ll talk about this later, but first we’ll talk about the most common cause of pain.

In most cases, pain is a signal that’s picked up by receptors in some part of the body, and from there it’s sent to your brain. So there’s three parts involved: The receptor, a long transmission channel that goes to the brain, and the brain itself. The most common cause of pain is that the pain receptors, which are called nociceptors, are triggered by cell damage.

What is pain good for? A clue comes from people who can’t feel pain. This is caused by rare genetic mutations that stop pain receptors or their transmission from working. It affects about 1 in 25 thousand people. Infants with this condition may try to chew off their tongue, lips, or fingers, and later accumulate bruises and broken bones.  So, pain is uncomfortable, but is actually good for something. It’s a warning signal that teaches you to not do some things. Still, sometimes you’d rather not have it, so let’s talk about ways to get rid of pain.

The most straightforward way to remove pain are local and regional anesthetics. Those are the ones you get at the dentist, but you also find them in lower doses in some creams. They take effect only at the place where you apply them, and they wear off as the body carries away and takes apart the substance.

Their names usually end in –caine. Like Benzocaine, Novocaine, and also cocaine. Yes, cocaine is a local anesthetic, and it had quite an interesting history, even before it ran wall-street in the 80s. Rohin did a great video about this. There are some exceptions to the nomenclature, such as naturally occurring anesthetics, including Menthol.

Local anesthetics prevent the pain signal from being created by changing the distribution of electric charges in cells. Cells use a difference in electric charges to create a signal. Normally, the outside of a nerve ending is slightly positively charged. With the right environmental trigger, channels open in the cell membrane and increase the number of positive charges inside. A local anesthetic blocks those cell channels, so the pain receptors can’t give alarm. But since *all nerve cells work this way, a local anesthetic doesn’t just take away the pain. It takes away all sensation. So the body part its applied to will feel completely numb.

This isn’t a good solution for any extended duration of time, which brings us to ways to stop the pain specifically and leave other sensation intact. Drugs which do that are called analgesics. To understand how they work, we’ll need a little more detail on what cell damage does.

When cells are damaged they release a chemical called arachidonic acid, which is then converted by certain enzymes into a type of prostaglandin. If someone had stopped me on the street last week and asked what prostaglandin is, I might have guessed it’s a small country in Europe. Turns out it’s yet another chemical that flows in your blood and it’s the one that causes swelling and redness. It also lowers the pain threshold. This means that with the prostaglandin around, the pain receptors fire very readily. And since the swelling can push on the pain receptors, they might fire a lot. So, well, it’ll hurt.

But the prostaglandin itself doesn’t live long in the body. It falls apart in about 30 seconds. This tells us that one way to stop the pain is to knock out the enzymes that create prostaglandin. This is what the most common painkillers do. They are called “nonsteroidal anti-inflammatory drugs”, NSAIDs (N said) for short. Some painkillers in this class are: ibuprofen, which is sold under brand names like Advil, Anadin or Norufen, acetylsalicylic acid that you may know as Aspirin, diclofenac which is the active ingredient in Voltaren and Dicloflex, and so on. I guess at some point pretty much all of us have awkwardly asked around for one of those.

How do they work? Magic. Thanks for watching. No wait. I’m just a physicist but I’ll do my best. The issue is, every article I read on biomedicine seems to come down to saying, there’s this thing which fits to that thing, and NSAIDs are no exception. These enzymes which they block come in two varieties called cox-1 and cox-2.  The painkillers work by latching into surface structures of those cox-enzymes which prevents the enzymes from doing their job. This means less prostaglandin is produced and the pain threshold goes back to normal. They don’t entirely turn pain off, like local anesthetics do, but you don’t feel pain that easily. And unlike local anesthetics, they work only on the pain receptors, not on other receptors.

Most of these pain killers block the cox enzymes temporarily and then fall off. Within a few hours, they’re usually out of the system and the pain comes back. The exception is Aspirin. Aspirin latches onto the coxes and then breaks off, taking them out permanently. The body has to produce new ones which takes time. This is why it takes much longer for the effects of aspirin to wear off, up to 10 days. Seriously. Aspirin is the weird cousin of the pain killers. The one that doesn't talk at family reunions but rearranges your bookshelf by color and 10 days later you haven’t fully recovered from that.

And of course there are side-effects. NSAIDs have a number of side effects in common because the type of prostaglandin which they block is necessary for some other things which they also inhibit. For example, you need it for keeping up the protective lining of the stomach and the rest of the digestive system. So long-term use of NSAIDs can cause stomach ulcers and inner bleeding. I know someone who took Aspirin regularly for years and had a stomach rupture. He survived but it was a *very close call. So, well, be careful.

NSAIDs also increase the risk of cardiovascular events. This doesn’t mean cardiologists will hold more conferences, though this risk also exists. No, cardiovascular events are things like strokes and heart attacks. If you wonder just how much NSAIDs increase the risk, that depends on just exactly which one you’re talking about. This table (3) lists the risk ratio for some common NSAIDs compared to a placebo. The relevant thing to pay attention to is that the numbers are almost all larger than 1. Not dramatically larger, but noticeably larger.

About 20 years ago research suggested that most of the adverse effects of NSAIDs come from blocking the COX-1 enzyme, while the effects that stop the pain come from the COX-2 enzyme. This is why several companies developed drugs to inhibit just the COX-2 enzyme, unlike traditional NSAIDs that block both versions.

These drugs are known as COXIBs. In theory, they should have been equally effective as painkillers as traditional NSAIDS but cause less problems with the digestive system. In practice, most of them were withdrawn from the market swiftly because they increased the risk of heart attacks even more than traditional NSAIDs. Some of them are still available because the risks are kind of similar.

NSAIDs are probably the most widely used over-the-counter painkillers and as you’ve seen scientists understand quite well how they work. Another widely used pain killer has however remained somewhat of a mystery: acetaminophen. In the US it’s sold under the brand name Tylenol, in Europe it’s Paracetamol.

And this brings me to the true reason I’m making this video. It’s because my friend Tim Palmer, the singing climate physicist, told me this joke. “Why is there no aspirin in the jungle? Because the paracetamol.” I didn’t understand this. And since I had nothing intelligent to say, I gave him a lecture about the difference between aspirin and paracetamol which eventually turned into this video. In case you also didn’t understand his joke, I’ll explain it later.

So what is the difference between NSAIDs and acetaminophen? For what pain relief is concerned, they’re kind of similar. Acetaminophen has the advantage that it’s easier on the digestive system. On the flipside, acetaminophen has a small active window, meaning the difference between the dose in which it has the desired effect and the dose where it’s seriously toxic is small, a factor of ten or so. Now take into account that acetaminophen is often added to other drugs, like cough syrup or drugs that help with menstrual cramps, and it becomes easy to accidentally overdose, especially in children. This is why child proof pill containers are so useful. Your children will not be able to open the pill bottle! And sometimes neither will you.

Acetaminophen is currently the most common cause of drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. Indeed, it’s one of the most common causes of poisoning worldwide. Since it’s removed from the body through the liver, the biggest risk is liver damage. In the developed world, acetaminophen overdose is currently the leading cause of acute liver failure.

Of course you generally shouldn’t mix medicine with alcohol, never ever, but especially not acetaminophen. You’ll get drunk very quickly, get a huge hangover, and run the risk of liver damage. Guess how I know. I had a friend who was doing all kinds of illegal drugs who said he doesn’t touch paracetamol – tells you all you need to know.

We’ve been talking about the pain receptors, but remember that there are three parts involved in pain. The receptor, the nerve wiring, and the brain. All of them can be a cause of pain. When pain is caused by damage to the nerve system it’s called neuropathic pain. This type of pain often doesn’t respond to over the counter drugs. It can be caused by direct nerve damage, but also by chemotherapy or diabetes and other conditions. The American National Academy of Sciences has estimated that in the United States neuropathic pain affects as much as one in three adults and leads to an annual loss of productivity exceeding 400 Billion US$.  That’s enough money to build a factory and make your own painkillers – on Mars!

Neuropathic pain and other pain that doesn’t go away with over-the-counter drugs is often treated with opioids. What are opioids and how do they work? Opioids are substances that were originally derived from poppies, but that can now be synthetically produced. They come in a large variety: morphine, codeine, oxycodone, heroine, fentanyl, etc. These don’t work exactly the same way, but the basic mechanism is more or less the same. I’m afraid the explanation is again pretty much that this thing fits to that thing.

The nervous system is equipped with receptors that opioids fit to, they are called – drums please – opioid receptors. These receptors can be occupied by endorphin, which is a substance that the human body produces, among other things to regulate pain. Opioids fit very well to those receptors. They can block them efficiently and for long periods of time. So, this is a very powerful way to reduce pain.

But opioids do a lot of other things in the human body, so there are side-effects. For one thing, opioids also suppress the release of noradrenaline, which is a hormone that among other things controls digestion, breathing, and blood pressure. Consequently, opioids can cause constipation or, in high doses, decrease heart and breathing rates to dangerously low levels. And, I mean, I’m not a doctor, but this doesn’t really sound good.

Opioids also act in the brain where they trigger the release of dopamine. Dopamine is often called the “feel good hormone” and that’s exactly what it does, it makes you feel good. That in and by itself isn’t all that much of a problem, the bigger problem is that the body adapts to the presence of opioids. Exactly what happens isn’t entirely clear, but probably the body decreases the number of opioid receptors and increases the number of receptors for the neurotransmitters that were suppressed. The consequence is that over time you have to increase the opioid dose to get the same results, to which the body adapts again, and so on. It’s a vicious cycle.

When you suddenly stop taking opioids, the number of many hormone receptors isn’t right. It takes time for the body to readjust and that causes a number of withdrawal symptoms, for example an abnormally high heart rate, muscle and stomach aches, fever, vomiting, and so on.

To keep opioid withdrawal symptoms manageable, the CDC recommend to reduce the dose slowly. If you’ve been taking opioids for more than a year, they say to reduce no more than a 10% per month. If you’ve been taking them for a few weeks or months, they recommend a 10% reduction per week. I’ll leave you a link to the CDC guide for how to safely get off opioids in the info below the video.

There are a number of other painkillers that don’t fall into either of these categories. Going through them would be rather tedious, but I want to briefly mention cannabis which has recently become increasingly popular for self-treatments of pain. A meta study published last year in the British Journal of Medicine looked at 32 trials involving over 5000 patients who took cannabis for periods ranging from a month up to half a year. They found that the effect of pain relief does exist, but it’s small.

Let then talk about the third body part that’s involved in pain, which is the brain. The brain plays a huge role in our perception of pain, and scientists are only just beginning to understand this.

A particularly amazing case was reported in the British Medical Journal in 1995. A 29-year-old construction worker was rushed to the emergency department of a hospital in Leicester. He’d jumped onto a 6-inch nail that had gone through the sole of his boot. This is an actual photo from the incident. The smallest movement of the nail was so painful that he was sedated with fentanyl and midazolam. The doctors pulled out the nail and took off the boot. And saw that the nail had gone through between the toes. The foot was entirely uninjured. He felt pain not because he actually had an injury, but because his brain was *convinced he had an injury. It’s called somatic amplification.

The opposite effect, somatic deamplification, also happens. Take for example this other accident that happened to another construction worker. Tthey aren’t paid enough these guys. This 23-year old man from Denver had somewhat of a blurry vision and a toothache. He went to a dentist. The dentist took an x-ray and conclude that the likely source of the toothache was that the man had a 4-inch nail in his skull. He’d probably accidentally shot himself with a nail gun but didn’t notice. Part of reason he wasn’t in more pain was probably that he just didn’t know he had a nail in his head.

Severe pain also changes the brain. It activates a brain region called the hypothalamus which reacts by increasing the levels of several hormones, for example cortisol and pregnenolone. This affects all kinds of things from blood sugar levels to fat metabolism to memory functions. The body is simply unable to produce these hormones at a high level for a long time. But some of those hormones are critical to pain control. A deficiency may enhance pain and slow down healing and may be one of the causes for chronic pain.

Another thing that happens if some part of your body hurts is that you learn incredibly quickly to not touch or move it. This has nothing to do with the signal itself, it’s an adaptation in the brain. This adaptation too, may have something to do with chronic pain. For example, several studies have shown that the severity of tinnitus is correlated with chronic pain, which suggests that some people are prone to develop such conditions, though the details aren’t well understood.

Indeed, scientists have only recently understood that the brain itself plays a big role in how severely we experience pain, something that can now be studied with brain scans. Consequently, some pain treatments have been proposed that target neither pain receptors nor the nervous system, but the brain response to the signals.

For example, there is the idea of audioanalgesia, that’s trying to reduce pain by listening to white noise or music. Or electroanalgesia, which uses electricity to interfere with the electric currents of pain signals. And some people use hypnosis to deal with pain. Does this actually work? We haven’t looked into it, but if you’re interested let us know in the comments and we’ll find out for you.