RESEARCH STARTER

Acetaminophen

Acetaminophen, also known as paracetamol, is a widely used over-the-counter analgesic that provides relief from mild to moderate pain, such as headaches and menstrual discomfort, while also acting as an antipyretic to reduce fever. It is particularly popular for its effectiveness and low gastrointestinal toxicity compared to other pain relievers like aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). Despite its safety profile, acetaminophen can lead to severe complications, such as liver failure, especially when misused or combined with alcohol. Its history dates back to the late 19th century, with significant advancements in understanding its therapeutic potential occurring in the mid-20th century.

Current research is exploring acetaminophen's broader applications, including its potential interactions with cardiovascular conditions and other diseases. Studies suggest that combining acetaminophen with certain NSAIDs could enhance its effectiveness. Although it is generally considered safe when used correctly, awareness of its risks, including the possibility of overdosing, is crucial for users. With ongoing research into its biological interactions, acetaminophen may continue to evolve in its clinical applications, maintaining its status as a leading choice for pain management.

Full Article

Acetaminophen, also called paracetamol, is an analgesic, or pain-relief drug, used primarily for body and menstrual aches, headaches, and other mild to moderate pain. One of the leading nonprescription drugs in the general treatment of minor pain for a wide range of ages, acetaminophen acts on the brain to reduce pain signals and cools the body as it provides relief. It is also an antipyretic used to reduce fevers and alleviate joint pain, such as that caused by osteoarthritis, although it is not recommended to treat the underlying inflammation, as the drug does not have noticeable anti-inflammatory effects. Acetaminophen’s expansive therapeutic effects are under examination for the drug’s interaction with a wider array of diseases. The use of acetaminophen in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac can lead to improved therapeutic effects and pain relief.

Brief History

During the Middle Ages, typical antipyretic agents were derived from cinchona bark and white willow bark, more commonly known as the chemical family of salicins. By the 1880s, the scarcity of the cinchona tree fueled the need for an alternative source for antipyretic agents. Harmon Northrop Morse first produced and unknowingly discovered acetaminophen in 1878 through the reduction of p-nitrophenol with tin in the presence of glacial acetic acid. Acetaminophen was not properly used for medical purposes until fifteen years later, when researchers justified its effectiveness as an antipyretic. However, initial trials showed acute toxicity in testing animals such as Hungarian frogs, guinea pigs, rabbits, and dogs. Given the troubling effects, acetaminophen did not receive any further interest until the 1940s.

In the late 1940s, researchers at Yale University determined that acetaminophen was the major metabolite of acetanilide, a known analgesic and antipyretic, and that, in fact, it was acetaminophen that was responsible for acetanilide’s efficacy. Soon after, biochemists Bernard Brodie and Julius Axelrod demonstrated acetaminophen’s analgesic effects on human volunteers and determined that it was less toxic than acetanilide, which was known to cause methemoglobinemia (elevated methemoglobin in the blood), and most likely safer than phenacetin, another acetanilide derivative that also metabolized into acetaminophen. The rediscovery of acetaminophen sparked public interest in the United States, where it was subsequently sold, in combination with aspirin and caffeine, under the trade name Triagesic. Within a year, Triagesic was withdrawn from the market after three users were reported to have been diagnosed with the blood disease agranulocytosis. However, it soon became apparent that the disease had not been caused by the acetaminophen, and by 1955, it had been reintroduced to the US market as a single nonprescription analgesic.

By the 1960s, acetaminophen proved its safety and reliability among its predecessors, particularly acetanilide and phenacetin, whose side effects included gastrointestinal ulceration and hemorrhage, among others. However, the ensuing widespread availability of the drug increased reports of self-overdose, and in 1966, the first cases of severe liver damage were reported in Scotland. Initially, the severity of the drug’s liver damage was misunderstood; liver abnormalities would only appear after three or four days of delay, and though many of the patients reported swift recoveries, a few developed acute liver failure within four to six days. In the 1970s, scientists discovered a breakthrough way of preventing acetaminophen’s conversion into a toxic metabolite, followed by the first successful treatment of critical acetaminophen poisoning with cysteamine and the presentation of N-acetylcysteine as the primary antidote to acetaminophen poisoning.

Acetaminophen Today

Acetaminophen is the prevailing antipyretic and analgesic against mild to moderate pain and symptoms. It is often used together with other pain medicines in clinical practice to improve overall pain control. Other chemical compounds, such as aspirin and other NSAIDs, are also available in similar doses, although these may have a higher risk of gastrointestinal side effects in some cases. Acetaminophen is increasingly used as a treatment for osteoarthritis, although a 2015 review by Gustavo C. Machado and colleagues found that it provided only “minimal short-term benefit” to patients with osteoarthritis, and has managed to maintain low gastrointestinal toxicity effects even at over-the-counter (OTC) doses. Although rare, serious acetaminophen complications can include liver failure or death, though these are usually related to self-medication and misuse of the drug. Such actions often lead to acetaminophen overdosing and toxicity, especially in relation to the combination of acetaminophen with alcohol, fasting, other drugs, or poor nutritional status. Health authorities have set clear limits on daily doses and warn against using multiple products containing acetaminophen at the same time.

The discovery of two cyclooxygenase (COX) enzymes, namely COX-1 and COX-2, has influenced the development of analgesic and anti-inflammatory drugs. Current and available drugs relate the majority of side effects to the inhibition of the enzyme COX-1, while effectiveness is related to the inhibition of COX-2, both of which play roles in physiological and inflammatory processes. Acetaminophen may also act in the central nervous system through a metabolite called AM404, which can affect cannabinoid receptors and pain pathways. The exact mechanism of acetaminophen is not fully understood and does not depend on a COX-3 pathway in humans. Some interactions between acetaminophen and NSAIDs have been studied, and combination therapy may improve pain relief.

Further examination into the therapeutic effects of acetaminophen in other areas of medicine may lead to vastly improved uses of the drug. Low-density lipoproteins (LDL) have a significant effect on the treatment of atherosclerosis, cardiovascular disease, and stroke. Higher LDL levels signify accumulation of fats on the walls of the body’s blood vessels, increasing the potential for blockage and sudden blood clots that can ultimately lead to a heart attack or stroke. Acetaminophen is not used to prevent cardiovascular disease.

Some laboratory studies have examined its effects on liver cells, but these findings are not used in clinical treatment. HepG2 cells are a long-lasting cell line derived from a hepatocellular carcinoma, the most common type of primary liver cancer.

Some research in the 2010s proposed the potential danger of using acetaminophen during pregnancy. Limited research indicated that the medication may cause neurodevelopmental disorders. However, further research in the 2020s found conflicting data, with no causal link between neurodevelopmental disorders and fetal acetaminophen exposure. Other studies in the 2020s found a link between fetal acetaminophen exposure and attention deficits and language delays in young children. Large population studies have not confirmed a direct cause-and-effect relationship, though careful use during pregnancy is advised.

Acetaminophen has long been one of the best-selling OTC analgesics, with no significant contradictory reports to hinder consumers from continuing its use. Its use increased during global viral outbreaks, including COVID-19, due to its role in managing fever and mild pain. The continuous and increasing understanding of the drug and its interactions with the human biological system can expand its utility for a broader range of clinical use.


Bibliography

“Acetaminophen.” MedlinePlus, 15 Oct. 2025, medlineplus.gov/druginfo/meds/a681004.html. Accessed 18 Mar. 2026.

“Acetaminophen (Oral Route, Rectal Route).” Mayo Clinic, 1 Feb. 2026, www.mayoclinic.org/drugs-supplements/acetaminophen-oral-route-rectal-route/description/drg-20068480. Accessed 18 Mar. 2026.

“Acetaminophen.” U.S. Food and Drug Administration, 14 Aug. 2025, www.fda.gov/drugs/information-drug-class/acetaminophen. Accessed 18 Mar. 2026.

Ahlqvist, Viktor H., et al. “Acetaminophen Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability.” JAMA, vol. 331, no. 14, 9 Apr. 2024, pp. 1205–14, doi:10.1001/jama.2024.3172. Accessed 19 Mar. 2026.

Botting, Robert M. “Inhibitors of Cyclooxygenases: Mechanisms, Selectivity and Uses.” Journal of Physiology and Pharmacology, vol. 57, suppl. 5, 2006, pp. 113–24, www.jpp.krakow.pl/journal/archive/11_06_s5/pdf/113_11_06_s5_article.pdf. Accessed 18 Mar. 2026.

Brown, Trevor, et al. “Pain Relief: From Coal Tar to Paracetamol.” Education in Chemistry, Royal Society of Chemistry, 1 July 2005, edu.rsc.org/feature/pain-relief-from-coal-tar-to-paracetamol/2020140.article. Accessed 18 Mar. 2026.

“Clinical Management of COVID-19: Living Guideline.” World Health Organization, 18 Aug. 2023, www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2023.2. Accessed 18 Mar. 2026.

“Don’t Overuse Acetaminophen.” U.S. Food and Drug Administration, 1 Feb. 2024, www.fda.gov/consumers/consumer-updates/dont-overuse-acetaminophen. Accessed 18 Mar. 2026.

Graham, Graeme G., et al. “The Modern Pharmacology of Paracetamol: Therapeutic Actions, Mechanism of Action, Metabolism, Toxicity and Recent Pharmacological Findings.” Inflammopharmacology, vol. 21, no. 3, 2013, pp. 201–32, doi:10.1007/s10787-013-0172-x. Accessed 18 Mar. 2026.

Javaherian, Atash, and Pasha Latifpour, editors. Acetaminophen: Properties, Clinical Uses, and Adverse Effects. Nova Science Publishers, 2012.

Liew, Zeyan, et al. “Acetaminophen Use during Pregnancy, Behavioral Problems, and Hyperkinetic Disorders.” JAMA Pediatrics, vol. 168, no. 4, 2014, pp. 313–20, doi:10.1001/jamapediatrics.2013.4914. Accessed 18 Mar. 2026.

Machado, Gustavo C., et al. “Efficacy and Safety of Paracetamol for Spinal Pain and Osteoarthritis: Systematic Review and Meta-Analysis of Randomised Placebo Controlled Trials.” The BMJ, vol. 350, 2015, article h1225, doi:10.1136/bmj.h1225. Accessed 18 Mar. 2026.

Prescott, Laurie F. “Paracetamol: Past, Present, and Future.” American Journal of Therapeutics, vol. 7, no. 2, 2000, pp. 143–47.

Williams, C. David, et al. “Protection against Acetaminophen-Induced Liver Injury by Allopurinol Is Dependent on Aldehyde Oxidase–Mediated Liver Preconditioning.” Toxicology and Applied Pharmacology, vol. 274, no. 3, 15 Dec. 2013, pp. 417–24, doi:10.1016/j.taap.2013.12.003. Accessed 18 Mar. 2026.

Full Article

Acetaminophen, also called paracetamol, is an analgesic, or pain-relief drug, used primarily for body and menstrual aches, headaches, and other mild to moderate pain. One of the leading nonprescription drugs in the general treatment of minor pain for a wide range of ages, acetaminophen acts on the brain to reduce pain signals and cools the body as it provides relief. It is also an antipyretic used to reduce fevers and alleviate joint pain, such as that caused by osteoarthritis, although it is not recommended to treat the underlying inflammation, as the drug does not have noticeable anti-inflammatory effects. Acetaminophen’s expansive therapeutic effects are under examination for the drug’s interaction with a wider array of diseases. The use of acetaminophen in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac can lead to improved therapeutic effects and pain relief.

Brief History

During the Middle Ages, typical antipyretic agents were derived from cinchona bark and white willow bark, more commonly known as the chemical family of salicins. By the 1880s, the scarcity of the cinchona tree fueled the need for an alternative source for antipyretic agents. Harmon Northrop Morse first produced and unknowingly discovered acetaminophen in 1878 through the reduction of p-nitrophenol with tin in the presence of glacial acetic acid. Acetaminophen was not properly used for medical purposes until fifteen years later, when researchers justified its effectiveness as an antipyretic. However, initial trials showed acute toxicity in testing animals such as Hungarian frogs, guinea pigs, rabbits, and dogs. Given the troubling effects, acetaminophen did not receive any further interest until the 1940s.

In the late 1940s, researchers at Yale University determined that acetaminophen was the major metabolite of acetanilide, a known analgesic and antipyretic, and that, in fact, it was acetaminophen that was responsible for acetanilide’s efficacy. Soon after, biochemists Bernard Brodie and Julius Axelrod demonstrated acetaminophen’s analgesic effects on human volunteers and determined that it was less toxic than acetanilide, which was known to cause methemoglobinemia (elevated methemoglobin in the blood), and most likely safer than phenacetin, another acetanilide derivative that also metabolized into acetaminophen. The rediscovery of acetaminophen sparked public interest in the United States, where it was subsequently sold, in combination with aspirin and caffeine, under the trade name Triagesic. Within a year, Triagesic was withdrawn from the market after three users were reported to have been diagnosed with the blood disease agranulocytosis. However, it soon became apparent that the disease had not been caused by the acetaminophen, and by 1955, it had been reintroduced to the US market as a single nonprescription analgesic.

By the 1960s, acetaminophen proved its safety and reliability among its predecessors, particularly acetanilide and phenacetin, whose side effects included gastrointestinal ulceration and hemorrhage, among others. However, the ensuing widespread availability of the drug increased reports of self-overdose, and in 1966, the first cases of severe liver damage were reported in Scotland. Initially, the severity of the drug’s liver damage was misunderstood; liver abnormalities would only appear after three or four days of delay, and though many of the patients reported swift recoveries, a few developed acute liver failure within four to six days. In the 1970s, scientists discovered a breakthrough way of preventing acetaminophen’s conversion into a toxic metabolite, followed by the first successful treatment of critical acetaminophen poisoning with cysteamine and the presentation of N-acetylcysteine as the primary antidote to acetaminophen poisoning.

Acetaminophen Today

Acetaminophen is the prevailing antipyretic and analgesic against mild to moderate pain and symptoms. It is often used together with other pain medicines in clinical practice to improve overall pain control. Other chemical compounds, such as aspirin and other NSAIDs, are also available in similar doses, although these may have a higher risk of gastrointestinal side effects in some cases. Acetaminophen is increasingly used as a treatment for osteoarthritis, although a 2015 review by Gustavo C. Machado and colleagues found that it provided only “minimal short-term benefit” to patients with osteoarthritis, and has managed to maintain low gastrointestinal toxicity effects even at over-the-counter (OTC) doses. Although rare, serious acetaminophen complications can include liver failure or death, though these are usually related to self-medication and misuse of the drug. Such actions often lead to acetaminophen overdosing and toxicity, especially in relation to the combination of acetaminophen with alcohol, fasting, other drugs, or poor nutritional status. Health authorities have set clear limits on daily doses and warn against using multiple products containing acetaminophen at the same time.

The discovery of two cyclooxygenase (COX) enzymes, namely COX-1 and COX-2, has influenced the development of analgesic and anti-inflammatory drugs. Current and available drugs relate the majority of side effects to the inhibition of the enzyme COX-1, while effectiveness is related to the inhibition of COX-2, both of which play roles in physiological and inflammatory processes. Acetaminophen may also act in the central nervous system through a metabolite called AM404, which can affect cannabinoid receptors and pain pathways. The exact mechanism of acetaminophen is not fully understood and does not depend on a COX-3 pathway in humans. Some interactions between acetaminophen and NSAIDs have been studied, and combination therapy may improve pain relief.

Further examination into the therapeutic effects of acetaminophen in other areas of medicine may lead to vastly improved uses of the drug. Low-density lipoproteins (LDL) have a significant effect on the treatment of atherosclerosis, cardiovascular disease, and stroke. Higher LDL levels signify accumulation of fats on the walls of the body’s blood vessels, increasing the potential for blockage and sudden blood clots that can ultimately lead to a heart attack or stroke. Acetaminophen is not used to prevent cardiovascular disease.

Some laboratory studies have examined its effects on liver cells, but these findings are not used in clinical treatment. HepG2 cells are a long-lasting cell line derived from a hepatocellular carcinoma, the most common type of primary liver cancer.

Some research in the 2010s proposed the potential danger of using acetaminophen during pregnancy. Limited research indicated that the medication may cause neurodevelopmental disorders. However, further research in the 2020s found conflicting data, with no causal link between neurodevelopmental disorders and fetal acetaminophen exposure. Other studies in the 2020s found a link between fetal acetaminophen exposure and attention deficits and language delays in young children. Large population studies have not confirmed a direct cause-and-effect relationship, though careful use during pregnancy is advised.

Acetaminophen has long been one of the best-selling OTC analgesics, with no significant contradictory reports to hinder consumers from continuing its use. Its use increased during global viral outbreaks, including COVID-19, due to its role in managing fever and mild pain. The continuous and increasing understanding of the drug and its interactions with the human biological system can expand its utility for a broader range of clinical use.


Bibliography

“Acetaminophen.” MedlinePlus, 15 Oct. 2025, medlineplus.gov/druginfo/meds/a681004.html. Accessed 18 Mar. 2026.

“Acetaminophen (Oral Route, Rectal Route).” Mayo Clinic, 1 Feb. 2026, www.mayoclinic.org/drugs-supplements/acetaminophen-oral-route-rectal-route/description/drg-20068480. Accessed 18 Mar. 2026.

“Acetaminophen.” U.S. Food and Drug Administration, 14 Aug. 2025, www.fda.gov/drugs/information-drug-class/acetaminophen. Accessed 18 Mar. 2026.

Ahlqvist, Viktor H., et al. “Acetaminophen Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability.” JAMA, vol. 331, no. 14, 9 Apr. 2024, pp. 1205–14, doi:10.1001/jama.2024.3172. Accessed 19 Mar. 2026.

Botting, Robert M. “Inhibitors of Cyclooxygenases: Mechanisms, Selectivity and Uses.” Journal of Physiology and Pharmacology, vol. 57, suppl. 5, 2006, pp. 113–24, www.jpp.krakow.pl/journal/archive/11_06_s5/pdf/113_11_06_s5_article.pdf. Accessed 18 Mar. 2026.

Brown, Trevor, et al. “Pain Relief: From Coal Tar to Paracetamol.” Education in Chemistry, Royal Society of Chemistry, 1 July 2005, edu.rsc.org/feature/pain-relief-from-coal-tar-to-paracetamol/2020140.article. Accessed 18 Mar. 2026.

“Clinical Management of COVID-19: Living Guideline.” World Health Organization, 18 Aug. 2023, www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2023.2. Accessed 18 Mar. 2026.

“Don’t Overuse Acetaminophen.” U.S. Food and Drug Administration, 1 Feb. 2024, www.fda.gov/consumers/consumer-updates/dont-overuse-acetaminophen. Accessed 18 Mar. 2026.

Graham, Graeme G., et al. “The Modern Pharmacology of Paracetamol: Therapeutic Actions, Mechanism of Action, Metabolism, Toxicity and Recent Pharmacological Findings.” Inflammopharmacology, vol. 21, no. 3, 2013, pp. 201–32, doi:10.1007/s10787-013-0172-x. Accessed 18 Mar. 2026.

Javaherian, Atash, and Pasha Latifpour, editors. Acetaminophen: Properties, Clinical Uses, and Adverse Effects. Nova Science Publishers, 2012.

Liew, Zeyan, et al. “Acetaminophen Use during Pregnancy, Behavioral Problems, and Hyperkinetic Disorders.” JAMA Pediatrics, vol. 168, no. 4, 2014, pp. 313–20, doi:10.1001/jamapediatrics.2013.4914. Accessed 18 Mar. 2026.

Machado, Gustavo C., et al. “Efficacy and Safety of Paracetamol for Spinal Pain and Osteoarthritis: Systematic Review and Meta-Analysis of Randomised Placebo Controlled Trials.” The BMJ, vol. 350, 2015, article h1225, doi:10.1136/bmj.h1225. Accessed 18 Mar. 2026.

Prescott, Laurie F. “Paracetamol: Past, Present, and Future.” American Journal of Therapeutics, vol. 7, no. 2, 2000, pp. 143–47.

Williams, C. David, et al. “Protection against Acetaminophen-Induced Liver Injury by Allopurinol Is Dependent on Aldehyde Oxidase–Mediated Liver Preconditioning.” Toxicology and Applied Pharmacology, vol. 274, no. 3, 15 Dec. 2013, pp. 417–24, doi:10.1016/j.taap.2013.12.003. Accessed 18 Mar. 2026.

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