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How Does Paracetamol Work?

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K S Lane is a student of pharmacology and has a deep and passionate interest in all kinds of ailments and medications.

Paracetamol, also known as acetaminophen, is one of the most widely used drugs in the world, and you probably don’t even realise that you’re taking it. It’s the key ingredient in a number of common tablets, including Panadol, Paralgin, Panamax, Calpol, Tipol and Tylenol. Though it’s not particularly strong, many people swear that popping one or two of these pills will completely diminish their headache, back pain, fever and other ailments. The invention of new products like Panadol Advance, Panadol Extra, Panadol Ultra and Panadol Help-we’ve-run-out-of-adjectives have only heightened paracetamol’s prevalence as a painkiller. But how does paracetamol actually work? What’s in it, who first discovered it, can it really target specific pain, and is its mass consumption taking a toll on global health?

How does paracetamol work? Keep scrolling to find out!

How does paracetamol work? Keep scrolling to find out!

What is Paracetamol?

Paracetamol, or acetaminophen, is an analgesic (pain relieving), antipyretic (fever reducing) drug. It has a chemical formula of C8H9NO2 and the scientific name n-(4-hydroxyphenyl)ethanamide— catchy, right? Its structure, as pictured below, contains a hydroxyl (alcohol) group, an amide group and a benzene ring.

The chemical structure of paracetamol (acetaminophen).

The chemical structure of paracetamol (acetaminophen).

Who First Discovered Paracetamol?

Paracetamol was first synthesised by a chemist called Harmon Northrop Morse (killer name, I know) in 1878, and was first put into commercial use in 1883. However, it wasn’t until the 1950s that it became the public’s pain killer of choice. Previously, it had always held second place a medication called phenacetin, but when phenacetin was booted off the market for causing cancer and renal (kidney) failure paracetamol secured the top slot. Interestingly, it was Morse who first synthesised phenacetin, also in 1878. Is that a cause for concern? I’ll let you decide that one for yourself.

An old chemistry kit-- likely similar to the one used by Harmon Northrop Morse in 1878 when he first synthesised paracetamol

An old chemistry kit-- likely similar to the one used by Harmon Northrop Morse in 1878 when he first synthesised paracetamol

How Does Paracetamol Work?

One of the most interesting things about paracetamol is that we don’t actually know how it works. Wait, what? Pretty much the entire population has used this drug at one point or another, and we don’t know how it works? How on earth is that possible? Frankly, because its safety record is pretty much exemplary, it’s effective most of the time and it makes pharmaceutical companies a very large pile of money each year, there hasn’t been all that much research into its mechanism of action. However, there are a few theories that have been proposed. I’ve listed three of them below:

1. It enhances endogenous cannabinoids:

The idea behind this theory is that paracetamol breaks down to a compound called p-aminophenol in the body, and then reacts with arachidonic acid to form a different compound called N-arachidonoylphenolamine (or AM404, if you want something pronounceable). AM404 increases levels of endogenous cannabinoids, which is a class of molecule that acts on cannabinoid receptors. If the term 'cannabinoid' made you instantly think of cannabis, then you’re on the right track. The THC found in marijuana also acts on this cannabinoid receptors. Don’t get too ahead of yourself though; this theory doesn’t suggest that taking a few tablets of acetaminophen will get you high The activation of cannabinoid receptors can have a diverse range of effects on the body, meaning that they can produce analgesic (pain relieving) effects without making you giggly or suddenly craving snacks. This theory doesn’t, however, explain why paracetamol relieves fever.

2. It inhibits prostaglandins:

There’s considerable evidence that paracetamol inhibits the synthesis of substances called prostaglandins (or PGs). This is again achieved through the drug’s interaction with cannabinoid receptors. Prostaglandins are produced in response to an infection or injury and are involved in the inflammatory response, which produces redness, swelling and a healthy dose of pain. Despite this, paracetamol is not considered an anti-inflammatory drug and isn’t prescribed for inflammatory conditions such as rheumatoid arthritis. One explanation for this is that paracetamol works on receptors in the central nervous system only, rather than the site of the pain. This would mean that it blocks pain signals to the brain, but doesn’t have any other anti-inflammatory effects.

3. It activates serotonin producing pathways:

Serotonin producing pathways are a key part of the pain system. Serotonin is a hormone with a diverse range of functions, but it’s generally accepted that it has an analgesic effect when it acts on receptors in the spinal cord. Thus, it can be said that by activating serotonin producing pathways paracetamol inhibits pain. This explanation of the drug’s effects is widely accepted, but interestingly doctors continue to prescribe certain anti-nausea drugs around the time of surgery that inhibit paracetamol from exerting this effect.

Which theory is right?

We may never know for certain which of paracetamol’s mechanisms contributes most strongly to its function. There’s solid evidence for all three explanations being the 'most correct' one, and scientists are largely divided. It’s most likely that the effect we feel after popping a few tablets of paracetamol is due to a combination of all three pathways. Perhaps the most dominant mechanism even varies from person to person. Without further, extensive research there’s no way of knowing.

Can Paracetamol Target Specific Pain?

Recently, there’s been a huge influx of medications that claim to be designed for one specific type of pain, whether that be back pain, headache pain, joint pain or the pain of rejection (kidding, though wouldn’t that be great?). However, there’s evidence that these products are nothing more than clever marketing. It can be pretty persuasive when a company shows ads with people in white coats marvelling at how a simple pain killer can be used to target pain in a specific place, but scientifically this just doesn’t hold up. Paracetamol, and other drugs like it, are distributed in the bloodstream. There’s no way to dictate where the bulk of the drug goes or which receptors it interacts with. Additionally, paracetamol-based products that claim to be faster acting really aren’t that fantastic. They may work three to five minutes faster than a normal tablet, but when you consider the fact that you might pay double for these supposed miracle pills the few minutes really doesn’t seem worth it. If you want to relieve your pain three minutes faster, try taking a normal tablet of Panadol or Tylenol three minutes earlier.

The claim that some paracetamol-based medications can relieve specific types of pain has no scientific basis.

The claim that some paracetamol-based medications can relieve specific types of pain has no scientific basis.

Does Paracetamol Have Side Effects?

Compared to some pain killers, paracetamol is a relatively safe drug when the proper dosage is adhered to. However, it’s because paracetamol is viewed as a being a harmless substance that people tend to ignore the recommended dosage and end up getting sick. Oh, the bitter irony. In large doses paracetamol can cause liver-intoxication. Cases like these have increased so dramatically over the past decade that it’s even been questioned whether drugs containing paracetamol should only be sold via prescription. Long-term use of paracetamol has also been linked by some studies to slightly increased risk of impaired kidney function and heart attacks. All in all, as long as you pay attention to the dosage then paracetamol seems to be fairly harmless. Then again, we still don’t know the details of the mechanism and it’s always possible that a drug has hidden side effects that go unnoticed for decades. Isn’t that a nice thought?

Even the safest seeming medications can be toxic if the correct dosage isn't taken-- such is the case with paracetamol.

Even the safest seeming medications can be toxic if the correct dosage isn't taken-- such is the case with paracetamol.

In Conclusion:

Paracetamol, also commonly known as acetaminophen, is one of the most widely used drugs in the world. It’s an analgesic and antipyretic, which means it relieves both pain and fever. The drug was first synthesised in 1878 by Harmon Northrop Morse, but only really started to gain traction in the mid 1900s. Paracetamol likely works due to a combination of a number of different mechanisms, including its effects on endogenous cannabinoids, serotonin-producing pathways and on the production of prostaglandins. Claims that paracetamol-based medications can somehow target specific types of aches and pains have no scientific basis, and "fast-acting" paracetamol tablets generally have a negligible difference to standard ones. Paracetamol is a largely benign drug with few side effects, but can lead to liver intoxication if ingested in large amounts and has also been linked to a slightly elevated risk of heart attacks and kidney problems. All in all, paracetamol is a fascinating drug, with a surprising amount of mystery surrounding the details of its workings.

Sources and further reading:

  • https://www.ncbi.nlm.nih.gov/pubmed/17227290
  • https://academic.oup.com/bjaed/article/14/4/153/293533
  • https://www.netdoctor.co.uk/medicines/aches-pains/a8055/panadol-paracetamol/
  • https://academic.oup.com/bjaed/article/14/4/153/293533
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789136/
  • https://www.sciencedirect.com/science/article/pii/S1569733910700965
  • https://www.nhs.uk/news/medication/is-long-term-paracetamol-use-not-as-safe-as-we-thought/
  • https://www.ncbi.nlm.nih.gov/pubmed/18811827
  • https://www.ncbi.nlm.nih.gov/pubmed/15662292

© 2018 K S Lane

Comments

Pamela Oglesby from Sunny Florida on July 20, 2018:

This is a interesting article, and I am glad I a not taking acetaminophen, however my husband does. I never tought to question this medication. Thanks for the informatio.

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