Contrasting Mechanisms between Paracetamol and Ibuprofen

Paracetamol and ibuprofen are two of the most common painkillers which you can get over the counter at a pharmacy and are widely available for purchase in many shops. But many people don't know the difference between the two, which means many people struggle to know what may be best for them.

Drug mechanisms:

1. Paracetamol

Paracetamol, sometimes sold under the names Tylenol, Panadol and many others, is used for various types of pain, from headaches, to tooth ache, to period pain. Although difficult to believe, the exact mechanisms of how paracetamol works are still not fully characterised, however, from the synthesis of paracetamol in 1880s, there is a lot we have learned about how this drug eases pain.

When a tissue is injured in the body, pain is felt because cells release arachidonic acid, converted by special COX1/2 enzymes into prostaglandins, which then sensitises pain nerves at the site of injury, and acts on the brain to amplify transmission of pain signals, making the pain very difficult to ignore in some patients.

Paracetamol, unlike ibuprofen, has little effect on the site of the injury to reduce pain, and instead acts in the central nervous system. The drug is a reducing agent to COX1/2 enzymes, inhibiting their activity, so prostaglandin production is decreased and pain nerves and transmission is not sensitised. This mechanism works best in the central nervous system compared to the peripheral injury site, as in the periphery, peroxide presence is much higher at the site of inflammation which weakens paracetamol's ability to inhibit COX enzymes. This explains why paracetamol works better in the brain, where peroxide levels are low, and also explains why paracetamol does not have a strong anti-inflammatory effect on the body like ibuprofen does, as ibuprofen works locally on inflammation.

However it is still debated whether paracetamol works best on either COX1 or COX2 enzymes to relieve pain, as studies show different results, with many concluding COX2 is affected more. A third COX enzyme, COX3, was hypothesised to explain paracetamol's actions, but shown to be more linked to canine physiology rather than in humans.

When paracetamol enters the brain, it is thought to be converted into AM404, which indirectly activates endocannabinoid receptors, reducing the transmission of pain signalling. In addition, paracetamol is thought to dampen pain nerve transmission by increasing serotonin release in the spinal cord. However some studies intending to prove these mechanisms of pain relief fail to gain significant data, highlighting again the ambiguity of paracetamol's mechanisms [1].

2. Ibuprofen

Ibuprofen, sometimes sold under the brand names Advil and Nurofen, is a member of the non-steroidal anti-inflammatory drugs (NSAIDS), where its inhibition of COX1/2 enzymes is much more characterised, where it prevents them from converting arachidonic acid into prostaglandins which cause inflammation and pain. Chronic inhibition of COX1 through ibuprofen use is linked to gastrointestinal issues like gut irritation as COX1 maintains the mucosa of this system.

Ibuprofen also inhibits COX enzymes in the central nervous system, not just the periphery, and reduces amplification of pain from prostaglandins.

It also reduces inflammation, a feature of this drug which is not present in paracetamol. By inhibiting prostaglandin production, it decreases the dilation of blood vessels and the production of cytokines which contribute to inflammation in the injury site, which is a source of pain itself, and can be swollen and tender to touch [2].

Appropriate drug for different pain types

It is always best to consult with a doctor or pharmacist about your drug options for a specific condition. However generally, ibuprofen is the better choice for pain associated with inflammation, like sprains, backaches and period pain, where there is swelling and inflammation and a potent COX inhibition to decrease prostaglandins is needed. It may also be more suitable for those with liver disease, as heavy paracetamol use can severely damage the liver, especially if already compromised.

Tissue damage associated with inflammation often will be accompanied by redness, swelling, warm skin, and pain that may be worse after inactivity, which can help with deciding which medication to take [3].

Paracetamol may be better for general headaches, as it works primarily in the central nervous system, and may be good for pains associated with illnesses like the flu, and can also reduce fevers due to it's actions in the brain. It is also more suitable for those who have stomach ulcers or bleeding disorders as NSAIDS may cause more harmful side effects in these patients and are not as well tolerated due to conflicting conditions [4].

Overdose

Overdoses in these drugs cause fundamentally different toxicities.

Paracetamol overdoses are considered more dangerous as they can cause liver failure by toxic products from paracetamol damaging liver cells, and in severe cases can lead to coma and death. It is also easier to overdose on paracetamol than ibuprofen as paracetamol has a more narrow therapeutic index, so the amount between a safe dose and a toxic dose is smaller than for ibuprofen. There is an antidote for paracetamol poisoning called NAC, allowing the liver to safely process toxic products from paracetamol metabolism, if given 4-8 hours after the overdose [5].

Ibuprofen overdoses affect the stomach lining, causing gastrointestinal diseases and stomach bleeding, as well as the causing kidney damage. This drug requires a much larger dose to be toxic, and any side effects are much more likely to be reversible, compared to the irreversible liver failure caused by a paracetamol overdose [6].

Further research

As emphasised, the mechanisms of how paracetamol work on the human body are still not fully known, despite decades of use and research. This is partly because animal studies in this area show vastly different effects than with humans when researching COX targets, along with the fact that it is difficult to quantify the importance of the many pathways paracetamol seems to affect.

Research into the exact mechanisms of paracetamol may allow us to understand liver toxicity better and develop better treatments or antidotes for overdoses. It would also potentially allow us to create and design different drugs that mimic the most beneficial effects of the drug, and allow us to treat other chronic pain conditions by researching the central pain pathways for further insight into how pain is processed in the brain.

References:

1. Ayoub SS. Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action. Temperature [Internet]. 2021 Mar 16;8(4):351–71. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8654482/

2. Blobaum AL, Marnett LJ. Structural and Functional Basis of Cyclooxygenase Inhibition. Journal of Medicinal Chemistry. 2007 Apr;50(7):1425–41.

3. Inflammatory Arthritis [Internet]. Hospital for Special Surgery. 2025. Available from: https://www.hss.edu/health-library/conditions-and-treatments/list/inflammatory-arthritis#symptoms

4. NHS. Common questions about paracetamol for adults [Internet]. nhs.uk. 2022. Available from: https://www.nhs.uk/medicines/paracetamol-for-adults/common-questions-about-paracetamol-for-adults/

5. Chidiac AS, Buckley NA, Noghrehchi F, Cairns R. Paracetamol (acetaminophen) Overdose and hepatotoxicity: mechanism, treatment, Prevention measures, and Estimates of Burden of Disease. Expert Opinion on Drug Metabolism and Toxicology. 2023;19(5):297–317.

6. Muhammed Ershad, Vearrier D. Ibuprofen Toxicity [Internet]. Nih.gov. StatPearls Publishing; 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526078/

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