Hubbry Logo
ParacetamolParacetamolMain
Open search
Paracetamol
Community hub
Paracetamol
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Paracetamol
Paracetamol
Paracetamol
View on Wikipedia
from Wikipedia

Paracetamol
Clinical data
PronunciationParacetamol: /ˌpærəˈsiːtəmɒl/ ⓘ
Acetaminophen: /əˌsiːtəˈmɪnəfɪn/ ⓘ
Trade namesTylenol, Panadol, others[1]
Other namesN-acetyl-para-aminophenol (APAP), acetaminophen (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa681004
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous, rectal
Drug class
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability63–89%[6]: 73 
Protein bindingnegligible to 10–25% in overdose[7]
MetabolismPredominantly in the liver[10]
MetabolitesAPAP gluc, APAP sulfate, APAP GSH, APAP cys, AM404, NAPQI[8]
Onset of actionOral: 37 minutes[9]
Intravenous: 8 minutes[9]
Elimination half-life1.9–2.5 hours[7]
ExcretionKidney[7]
Identifiers
  • N-(4-hydroxyphenyl)acetamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.002.870 Edit this at Wikidata
Chemical and physical data
FormulaC8H9NO2
Molar mass151.165 g·mol−1
3D model (JSmol)
Density1.293 g/cm3
Melting point169 °C (336 °F) [11][12]
Solubility in water
  • 7.21 g/kg (0 °C)[13]
  • 8.21 g/kg (5 °C)[13]
  • 9.44 g/kg (10 °C)[13]
  • 10.97 g/kg (15 °C)[13]
  • 12.78 g/kg (20 °C)[13]
  • ~14 mg/ml (20 °C)
  • CC(=O)Nc1ccc(O)cc1
  • InChI=1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10)
  • Key:RZVAJINKPMORJF-UHFFFAOYSA-N

Paracetamol,[a] or acetaminophen,[b] is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain.[14][15] It is a widely available over-the-counter drug sold generically or under various various brand names, including Tylenol and Panadol.

Paracetamol relieves pain in both acute mild migraine and episodic tension headache.[16][17] At a standard dose, paracetamol slightly reduces fever,[14][18][19] though it is inferior to ibuprofen in that respect[20] and the benefits of its use for fever are unclear, particularly in the context of fever of viral origins.[21] The aspirin/paracetamol/caffeine combination also helps with both conditions when the pain is mild and is recommended as a first-line treatment for them.[22] Paracetamol is effective for pain after wisdom tooth extraction, but it is less effective than ibuprofen.[23] The combination of paracetamol and ibuprofen provides greater analgesic efficacy than either drug alone.[23][24] The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant.[15][25] Evidence supporting its use in low back pain, cancer pain, and neuropathic pain is insufficient.[15][26][27][28][29][30] Paracetamol is the first-line treatment for pain and fever in pregnancy; no causal association with neurodevelopmental disorders has been established, while untreated pain and fever can harm the mother and fetus.[31][32][33]

In the short term, paracetamol is safe and effective when used as directed.[34] Short term adverse effects are uncommon and similar to ibuprofen.[35] Paracetamol is typically safer than nonsteroidal anti-inflammatory drugs (NSAIDs) for long-term use.[36] Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen.[37][38] Chronic consumption of paracetamol may result in a drop in hemoglobin level, indicating possible gastrointestinal bleeding,[39] and abnormal liver function tests. The recommended maximum daily dose for an adult is three to four grams.[26][40] Higher doses may lead to toxicity, including liver failure.[41] Paracetamol poisoning is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.[42][43][44]

Paracetamol was first made in 1878 by Harmon Northrop Morse or possibly in 1852 by Charles Frédéric Gerhardt.[45][46][47] It is the most commonly used medication for pain and fever in both the United States and Europe.[48] It is on the World Health Organization's List of Essential Medicines.[49] Paracetamol is available as a generic medication, with brand names including Tylenol and Panadol among others.[50] In 2023, it was the 112th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[51][52]

Medical uses

[edit]

Fever

[edit]

Paracetamol is used for reducing fever.[53] However, there has been a lack of research on its antipyretic properties, particularly in adults, and thus its benefits are unclear.[14] As a result, it has been described as over-prescribed for this application.[14] In addition, low-quality clinical data indicates that when used for the common cold, paracetamol may relieve a stuffed or runny nose, but not other cold symptoms such as sore throat, malaise, sneezing, or cough.[54]

For people in critical care, paracetamol decreases body temperature by only 0.2–0.3 °C more than control interventions and has no effect on their mortality.[18] It did not change the outcome in febrile patients with stroke.[55] The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported.[18] Paracetamol offered no benefit in the treatment of dengue fever and was accompanied by a higher rate of liver enzyme elevation: a sign of potential liver damage.[56] Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection.[21]

The efficacy of paracetamol in children with fever is unclear.[57] Paracetamol should not be used solely to reduce body temperature; however, it may be considered for children with fever who appear distressed.[58] It does not prevent febrile seizures.[58][59] It appears that 0.2 °C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergencies.[14] Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7 °C.[19] Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis[60]), including children younger than 2 years old,[61] with equivalent safety.[20] Exacerbation of asthma occurs with similar frequency for both medications.[62]

Pain

[edit]

Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, and toothache, as well as pain caused by cold, flu, sprains, and dysmenorrhea.[63] It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient.[15]

Musculoskeletal pain

[edit]

The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain.[15]

It appears to provide only small and not clinically important benefits in osteoarthritis.[15][26] American College of Rheumatology and Arthritis Foundation guideline for the management of osteoarthritis notes that the effect size in clinical trials of paracetamol has been very small, which suggests that for most individuals it is ineffective.[25] The guideline conditionally recommends paracetamol for short-term and episodic use to those who do not tolerate nonsteroidal anti-inflammatory drugs. For people taking it regularly, monitoring for liver toxicity is required.[25] Essentially the same recommendation was issued by European League Against Rheumatism (EULAR) for hand osteoarthritis.[64] Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only.[65]

Paracetamol is ineffective for acute low back pain.[15][27] No randomized clinical trials evaluated its use for chronic or radicular back pain, and the evidence in favor of paracetamol is lacking.[28][26][27]

Headaches

[edit]

Paracetamol is effective for acute migraine:[16] 39% of people experience pain relief at one hour compared with 20% in the control group.[66] The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a first-line treatment for migraine".[22] Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently.[17] However, the aspirin/paracetamol/caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: two hours after administering the medication, 29% of those who took the combination were pain-free as compared with 21% on paracetamol and 18% on placebo.[67] The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend this combination as a "highlighted" one for self-medication of tension headache, with paracetamol/caffeine combination being a "remedy of first choice", and paracetamol a "remedy of second choice".[68]

Dental and other post-surgical pain

[edit]

Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain.[69] For the relief of such pain, paracetamol is inferior to ibuprofen.[23] Full therapeutic doses of nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen, or diclofenac are clearly more efficacious than the paracetamol/codeine combination which is frequently prescribed for dental pain.[70] The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone.[23][24][71][72] Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations.[24]

A meta-analysis of general post-surgical pain, which included dental and other surgery, showed the paracetamol/codeine combination to be more effective than paracetamol alone: it provided significant pain relief to as much as 53% of the participants, while the placebo helped only 7%.[73]

Other pain

[edit]

Paracetamol fails to relieve procedural pain in newborn babies.[74][75] For perineal pain postpartum paracetamol appears to be less effective than nonsteroidal anti-inflammatory drugs (NSAIDs).[76]

The studies to support or refute the use of paracetamol for cancer pain and neuropathic pain are lacking.[29][30] There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department.[77] The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain.[78]

Use in pregnancy and breastfeeding

[edit]

Pregnancy

[edit]

Paracetamol has long been established as a safe medication to treat short-term fever and significant pain in pregnant patients. Regulatory agencies, including the European Medicines Agency (EMA),[79] the Medicines and Healthcare products Regulatory Agency (MHRA),[80] the World Health Organization (WHO),[81] and the U.S. Food and Drug Administration (FDA)[82] recommend paracetamol as a first-line analgesic and antipyretic in pregnancy, with use limited to situations where necessary, at the lowest effective dose, and for the shortest duration. High-quality clinical studies in humans have not demonstrated teratogenic or fetotoxic effects of paracetamol.

Some observational studies have suggested a possible association between prenatal paracetamol use and neurodevelopmental disorders, including ADHD and autism. However, these studies are limited by confounding factors such as maternal fever and infection, and do not demonstrate causation.[83][84][85][86]

Large, well-controlled studies, including sibling-controlled analyses, find no causal link after adjusting for maternal conditions.[83][87][85][86]

Untreated pain and fever can harm mother and fetus.[32][31]

Breastfeeding

[edit]

Paracetamol is excreted in breast milk at measurable concentrations (milk/plasma ratio approximately 1), but the amount ingested by the infant is much lower than pediatric therapeutic doses and rarely associated with clinical effects.[88][89] Use during breastfeeding is considered compatible at recommended doses, with extra caution for preterm infants or infants with liver disease.[90]

Patent ductus arteriosus

[edit]

Paracetamol helps ductal closure in patent ductus arteriosus. It is as effective for this purpose as ibuprofen or indomethacin, but results in less frequent gastrointestinal bleeding than ibuprofen.[91] Its use for extremely low birth weight and gestational age infants however requires further study.[91]

Adverse effects

[edit]

Gastrointestinal adverse effects such as nausea and abdominal pain are extremely uncommon, and their frequency is substantially lower than with ibuprofen use.[38] Increase in risk-taking behavior is possible.[92] According to the U.S. Food and Drug Administration (FDA), the drug may cause rare and possibly fatal skin reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis,[93] Rechallenge tests and an analysis of American but not French pharmacovigilance databases indicated a risk of these reactions.[93][94]

In clinical trials for osteoarthritis, the number of participants reporting adverse effects was similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain.[95] After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating gastrointestinal bleeding was observed in 20% of participants, this rate being similar to the ibuprofen group.[39]

Due to the absence of controlled studies, most of the information about the long-term safety of paracetamol comes from observational studies.[38] These indicate a consistent pattern of increased mortality as well as cardiovascular (stroke, myocardial infarction), gastrointestinal (ulcers, bleeding) and renal adverse effects with increased dose of paracetamol.[39][38][96] Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer.[38] Those who take it regularly at a higher dose (more than 2–3 g daily) are at much higher risk (3.6–3.7 times) of gastrointestinal bleeding and other bleeding events.[97] Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23%[98] and kidney cancer by 28%.[96] Paracetamol slightly but significantly increases blood pressure and heart rate.[38] A review of available research has suggested that increase in systolic blood pressure and increased risk of gastrointestinal bleeding associated with chronic paracetamol use shows a degree of dose dependence.[97]

The association between paracetamol use and asthma in children has been a matter of controversy.[99] However, the most recent research suggests that there is no association,[100] and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer, ibuprofen.[62]

In recommended doses, the side effects of paracetamol are mild to non-existent.[101] In contrast to aspirin, it is not a blood thinner (and thus may be used in patients where bleeding is a concern), and it does not cause gastric irritation.[102] Compared to Ibuprofen—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects.[103] Prolonged daily use may cause kidney or liver damage.[102][104] Paracetamol is metabolized by the liver and is hepatotoxic; side effects may be more likely in chronic alcoholics or patients with liver damage.[101][105]

Overdose

[edit]
Main article: Paracetamol poisoning

Overdose of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams),[40] and can cause potentially fatal liver damage.[106][107] A single dose should not exceed 1000 mg, doses should be taken no sooner than four hours apart, and no more than four doses (4000 mg) in 24 hours.[40] While a majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to the use of more than one paracetamol-containing product over an extended period.[108]

Paracetamol is hepatotoxic and depletes the stock of the antioxidant glutathione in the liver as glutathione is consumed much faster than it can be replenished.

Paracetamol toxicity has become the foremost cause of acute liver failure in the United States by 2003,[44] and as of 2005, paracetamol accounted for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.[109] As of 2004, paracetamol overdose resulted in more calls to poison control centers in the U.S. than overdose of any other pharmacological substance.[110] According to the FDA, in the United States, "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year [were] related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25% of the emergency department visits, 10% of the hospitalizations, and 25% of the deaths."[111][needs update]

Overdoses are frequently related to high-dose recreational use of prescription opioids, as these opioids are most often combined with paracetamol.[112] The overdose risk may be heightened by frequent consumption of alcohol.[113]

Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or non-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain as acute liver failure starts.[114] People who take overdoses of paracetamol do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by the drug.[115][116]

Treatment is aimed at removing the paracetamol from the body and replenishing glutathione.[116] Activated charcoal can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote, acetylcysteine (also called N-acetylcysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to prevent or at least decrease the possible damage to the liver; a liver transplant is often required if damage to the liver becomes severe.[42][117]

NAC was usually given following a treatment nomogram (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice.[118][119] Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it.[116] Kidney failure is also a possible side effect.[113]

Interactions

[edit]

Prokinetic agents such as metoclopramide accelerate gastric emptying, shorten time (tmax) to paracetamol peak blood plasma concentration (Cmax), and increase Cmax. Medications slowing gastric emptying such as propantheline and morphine lengthen tmax and decrease Cmax.[120][121] The interaction with morphine may result in patients failing to achieve the therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear.[121]

There have been suspicions that cytochrome inducers may enhance the toxic pathway of paracetamol metabolism to NAPQI (see Paracetamol#Pharmacokinetics). By and large, these suspicions have not been confirmed.[121] Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for phenobarbital, primidone, isoniazid, and possibly St John's wort.[122] On the other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%.[121]

Ranitidine increased paracetamol area under the curve (AUC) 1.6-fold. AUC increases are also observed with nizatidine and cisapride. The effect is explained by these drugs inhibiting glucuronidation of paracetamol.[121]

Paracetamol raises plasma concentrations of ethinylestradiol by 22% by inhibiting its sulfation.[121] Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week.[123][124][125]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Paracetamol appears to exert its effects through two mechanisms: the inhibition of cyclooxygenase (COX) and actions of its metabolite N-arachidonoylphenolamine (AM404).[126]

Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting COX-1 and COX-2 enzymes and especially similar to selective COX-2 inhibitors.[127] Paracetamol inhibits prostaglandin synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of arachidonic acid and peroxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight.[126][127]

The second mechanism centers on the paracetamol metabolite AM404. This metabolite has been detected in the brains of animals and cerebrospinal fluid of humans taking paracetamol.[126][128] It is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase.[126] AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor.[126] This and other research indicate that the endocannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol.[126][129]

In 2018, Suemaru et al. found that, in mice, paracetamol exerts an anticonvulsant effect by activation of the TRPV1 receptors[130] and a decrease in neuronal excitability by hyperpolarization of neurons.[131] The exact mechanism of the anticonvulsant effect of paracetamol is not clear. According to Suemaru et al., acetaminophen and its active metabolite AM404 show a dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice.[130]

In 2025, Maatuf et al. reported that AM404 is also produced by peripheral sensory neurons in vitro and blocks the action of pain-sensing Nav1.8 and 1.7 channels at nanomolar concentrations. AM404 injected into the hind paw of rats increase the pain threshold for the treated paw, but not the untreated paw, confirming the peripheral nature of this effect. It also lowers pain responses in a few other in vivo models when injected directly into the affected area. Other tested metabolites of paracetamol do not block pain-sensing sodium channels in vitro.[132][133]

Pharmacokinetics

[edit]

After being taken by mouth, paracetamol is rapidly absorbed from the small intestine, while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach's emptying and absorption, but the total amount absorbed stays the same.[134] In the same subjects, the peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate (but not high protein or high fat) food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours.[7]

Paracetamol's bioavailability is dose-dependent: it increases from 63% for 500 mg dose to 89% for 1000 mg dose.[7] Its plasma terminal elimination half-life is 1.9–2.5 hours,[7] and volume of distribution is roughly 50 L.[135] Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21%.[7] The concentration in serum after a typical dose of paracetamol usually peaks below 30 μg/mL (200 μmol/L).[136] After 4 hours, the concentration is usually less than 10 μg/mL (66 μmol/L).[136]

Important pathways of paracetamol metabolism

Paracetamol is metabolized primarily in the liver, mainly by glucuronidation and sulfation, and the products are then eliminated in the urine (see the Scheme on the right). Only 2–5% of the drug is excreted unchanged in the urine.[7] Glucuronidation by UGT1A1 and UGT1A6 accounts for 50–70% of the drug metabolism. Additional 25–35% of paracetamol is converted to sulfate by sulfation enzymes SULT1A1, SULT1A3, and SULT1E1.[137]

A minor metabolic pathway (5–15%) of oxidation by cytochrome P450 enzymes, mainly by CYP2E1, forms a toxic metabolite known as NAPQI (N-acetyl-p-benzoquinone imine).[137] NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with glutathione. The non-toxic conjugate APAP-GSH is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by a large amount of formed NAPQI, and NAPQI binds to mitochondria proteins of the liver cells causing oxidative stress and toxicity.[137]

Yet another minor but important direction of metabolism is deacetylation of 1–2% of paracetamol to form p-aminophenol. p-Aminophenol is then converted in the brain by fatty acid amide hydrolase into AM404, a compound that may be partially responsible for the analgesic action of paracetamol.[135]

Chemistry

[edit]

Synthesis

[edit]

Classical methods

[edit]

The classical methods for the production of paracetamol involve the acetylation of 4-aminophenol with acetic anhydride as the last step. They differ in how 4-aminophenol is prepared. In one method, nitration of phenol with nitric acid affords 4-nitrophenol, which is reduced to 4-aminophenol by hydrogenation over Raney nickel. In another method, nitrobenzene is reduced electrolytically giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by Tin(II) Chloride in absolute ethanol or ethyl acetate to produce a 91% yield of 4-aminophenol.[138][139][140]

Classical methods for the production of paracetamol

Celanese synthesis

[edit]

An alternative industrial synthesis developed at Celanese involves firstly direct acylation of phenol with acetic anhydride in the presence of hydrogen fluoride to a ketone, then the conversion of the ketone with hydroxylamine to a ketoxime, and finally the acid-catalysed Beckmann rearrangement of the cetoxime to the para-acetylaminophenol product.[138][141]

Celanese method for the preparation of paracetamol

Reactions

[edit]
Paracetamol crystals (crystallized from an aqueous solution) under a microscope
Close-up image of Paracetamol crystals produced by acetylation of 4-aminophenol

4-Aminophenol may be obtained by the amide hydrolysis of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, 4-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an indophenol dye under oxidization by air.[142]

History

[edit]
Julius Axelrod (pictured) and Bernard Brodie demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better-tolerated analgesic.

Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by Cahn & Hepp in 1886.[143] But its unacceptable toxic effects—the most alarming being cyanosis due to methemoglobinemia, an increase of hemoglobin in its ferric [Fe3+] state, called methemoglobin, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue—prompted the search for less toxic aniline derivatives.[144] Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.[46][47]

Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877,[145][146] but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans.[144] In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.[147] Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company.[148]

Von Mering's claims remained essentially unchallenged for half a century until two teams of researchers from the United States analysed the metabolism of acetanilide and phenacetin.[148] In 1947, David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.[149] In 1948, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor.[150][151][152] They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.[153] This led to a "rediscovery" of paracetamol.[144]

Paracetamol was first marketed in the United States in 1950 under the name Trigesic, a combination of paracetamol, aspirin, and caffeine.[146] Reports in 1951 of three users stricken with the blood disease agranulocytosis led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected.[146] The following year, 1952, paracetamol returned to the U.S. market as a prescription drug.[154] In the United Kingdom, marketing of paracetamol began in 1956 by Sterling-Winthrop Co. as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers.[155][156] In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.[155][146]

Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of analgesic nephropathy and hematological toxicity.[144] Available in the U.S. without a prescription since 1955[154] (1960, according to another source[157]), paracetamol has become a common household drug.[citation needed] In 1988, Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994.[158]

In June 2009, an FDA advisory committee recommended that new restrictions be placed on paracetamol use in the United States to help protect people from the potential toxic effects. The maximum single adult dosage would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and other products would be prohibited. Committee members were particularly concerned by the fact that the then-present maximum dosages of paracetamol had been shown to produce alterations in liver function.[159]

In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325 mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk of severe liver damage.[160][161][162][163][164] Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.[161][163]

In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.[165]

In September 2013, "Use Only as Directed", an episode of the radio program This American Life[166] highlighted deaths from paracetamol overdose. This report was followed by two reports by ProPublica alleging that the "FDA has long been aware of studies showing the risks of acetaminophen. So has the maker of Tylenol, McNeil Consumer Healthcare, a division of Johnson & Johnson"[167] and "McNeil, the maker of Tylenol, … has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."[168]

In September 2025, US President Donald Trump and HHS Secretary Robert F. Kennedy Jr. claimed that Tylenol may cause autism and urged pregnant women to avoid it; medical experts, major health organizations, and international studies strongly dispute any causal link, emphasizing that the drug remains safe for treating pain and fever in pregnancy.[169]

Society and culture

[edit]
Awareness poster on acetaminophen abuse as issued by the FDA

Naming

[edit]

Paracetamol is the Australian Approved Name[170] and British Approved Name[171] as well as the international nonproprietary name used by the WHO and in many other countries; acetaminophen is the United States Adopted Name[171] and Japanese Accepted Name and also the name generally used in Canada,[171] Venezuela, Colombia, and Iran.[171][172] Both paracetamol and acetaminophen are contractions of chemical names for the compound. The word "paracetamol" is a shortened form of para-acetylaminophenol,[173] and was coined by Frederick Stearns & Co in 1956,[174] while the word "acetaminophen" is a shortened form of N-acetyl-p-aminophenol (APAP), which was coined and first marketed by McNeil Laboratories in 1955.[175] The initialism APAP is used by dispensing pharmacists in the United States.[176]

Available forms

[edit]
See also: Paracetamol brand names

Paracetamol is available in oral, suppository, and intravenous forms.[177] Intravenous paracetamol is sold under the brand name Ofirmev in the United States.[178]

In some formulations, paracetamol is combined with the opiate codeine, sometimes referred to as co-codamol (BAN) and Panadeine in Australia. In the U.S., this combination is available only by prescription.[179] As of 1 February 2018, medications containing codeine also became prescription-only in Australia.[180] Paracetamol is also combined with other opioids such as dihydrocodeine,[181] referred to as co-dydramol (British Approved Name (BAN)), oxycodone[182] or hydrocodone.[183] Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate.[184] A combination of paracetamol, codeine, and the doxylamine succinate is also available.[185] Paracetamol is also available combined with butalbital and caffeine as a treatment for tension and migraine headaches.[186]

Paracetamol is sometimes combined with phenylephrine hydrochloride.[187] Sometimes a third active ingredient, such as ascorbic acid,[187][188] caffeine,[189][190] chlorpheniramine maleate,[191] or guaifenesin[192][193][194] is added to this combination.

  • Tylenol 500 mg capsules
    Tylenol 500 mg capsules
  • Panadol 500 mg tablets
    Panadol 500 mg tablets
  • For comparison: The pure drug is a colourless crystalline powder.
    For comparison: The pure drug is a colourless crystalline powder.

Veterinary use

[edit]
Brown tree snake aerial bait cartridges consisting of dead mice with 80 mg paracetamol tablets

Cats

[edit]

Paracetamol is extremely toxic to cats, which lack the necessary UGT1A6 enzyme to detoxify it. Initial symptoms include vomiting, salivation, and discoloration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, methemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation (methemoglobinemia and hemolytic anemia).[195] Treatment of the toxicosis with acetylcysteine is recommended.[196]

Dogs

[edit]

Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.[197] A paracetamol–codeine product (brand name Pardale-V)[198] licensed for use in dogs is available for purchase under supervision of a veterinarian, pharmacist or other qualified person.[198] It should be administered to dogs only on veterinary advice and with extreme caution.[198]

The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.[196][199][200][201] Acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.[196][197]

Snakes

[edit]

Paracetamol is lethal to snakes[202] and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam.[203][204] Doses of 80 mg are inserted into dead mice that are scattered by helicopter[205] as lethal bait to be consumed by the snakes.

Notes

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Paracetamol

View on Grokipedia
from Grokipedia
Paracetamol, also known as acetaminophen, is a synthetic non-opioid and medication that exerts its effects primarily through central mechanisms, including activation of descending serotonergic pathways, to relieve mild to moderate pain and reduce fever. First synthesized in 1878 by American chemist from p-nitrophenol, it remained largely overlooked until the and , when studies demonstrated its superior safety over related derivatives like , leading to its commercialization as a preferred alternative for everyday use. Widely recommended as a first-line treatment for pain by the due to its efficacy and low incidence of gastrointestinal side effects compared to non-steroidal anti-inflammatory drugs, paracetamol is available over-the-counter in many countries but carries a narrow margin of safety in overdose, where excessive dosing depletes hepatic and promotes formation of the toxic metabolite N-acetyl-p-benzoquinone imine (), resulting in —the most common cause of drug-induced in nations like the and . While therapeutic doses pose minimal risk of hepatotoxicity even in patients with , intentional or accidental overdoses exceeding 150 mg/kg in adults necessitate prompt intervention with N-acetylcysteine to mitigate severe outcomes.

Chemical Properties

Molecular Structure and Properties

Paracetamol, chemically known as N-(4-hydroxyphenyl), possesses the molecular formula C8H9NO2 and a molecular weight of 151.16 g/mol. Its structure features a benzene ring with a hydroxyl group (-OH) and an acetamido group (-NHCOCH3) attached in the para position, contributing to its classification as a para-aminophenol derivative. VSEPR theory predicts the following local geometries around key atoms in the molecule: trigonal planar for the benzene ring carbons (sp² hybridization, three electron domains), bent for the hydroxy oxygen (AX₂E₂, bond angle ≈109°), trigonal planar for the amide nitrogen (effective three electron domains due to resonance delocalization of the lone pair; basic VSEPR would predict trigonal pyramidal for four domains but resonance enforces planarity), trigonal planar for the carbonyl carbon (AX₃), and tetrahedral for the methyl carbon in the acetyl group (AX₄). The aromatic ring and amide group are largely planar due to conjugation. Paracetamol appears as a white, odorless crystalline powder at . It has a of 169–170.5 °C and a of 1.293 g/cm³. The compound exhibits limited in water, approximately 1.4 g/100 mL at 20 °C or 1 part in 70 at ambient conditions, increasing to 1 part in 20 at 100 °C; it is more soluble in (1:7) and acetone. Its boiling point exceeds 500 °C, indicating high thermal stability. In terms of acid-base properties, paracetamol displays a pKa of approximately 9.5 for the phenolic hydroxyl group, reflecting weak acidity characteristic of . The molecule is achiral and does not exhibit optical activity. Crystal structure analyses reveal a monoclinic lattice, influencing its polymorphic forms relevant to pharmaceutical formulations.

Synthesis Methods

Paracetamol was first synthesized in 1877 by American chemist through the reduction of p-nitrophenol using tin and , followed by . This method involved treating p-nitrophenol with tin in glacial acetic acid to yield p-aminophenol intermediate, which was then acetylated with to form paracetamol. Earlier claims attribute its preparation to Charles Frédéric Gerhardt in 1852 via similar reduction of phenylacetamide, but Morse's work is widely recognized as the definitive first synthesis. In laboratory settings, paracetamol is commonly prepared via a two-step process starting from p-nitrophenol: to p-aminophenol using reducing agents like iron or catalytic , followed by N-acetylation with in aqueous or acidic conditions. This route achieves high yields, often exceeding 80%, and illustrates and reduction chemistries. Industrial production predominantly employs the of p-aminophenol, sourced from the of phenol to p-nitrophenol (selectivity around 60-70% para ), followed by reduction using hydrogen over catalysts like or . The step reacts p-aminophenol with or at 80-100°C, yielding paracetamol with purity greater than 99% after from . This process, scaled globally in facilities across , , and , accounts for the majority of the estimated 100,000+ tons annual output, minimizing ortho-nitrophenol byproducts through optimized conditions. An alternative industrial route, the Hoechst-Celanese process introduced in the 1980s, starts from phenol via or to 4-hydroxyacetophenone (4-HAP). The 4-HAP is then oximated with to form the , which undergoes acid-catalyzed to directly yield paracetamol, bypassing the aminophenol intermediate and reducing waste from nitro reductions. This method improves , with overall yields up to 90%, and has been adopted for its efficiency in producing high-purity product without heavy metal catalysts. Emerging sustainable routes explore biomass-derived precursors, such as p-hydroxybenzoic acid from , converted via to p-aminophenol then , aiming to replace feedstocks. However, these remain non-dominant due to cost and scalability challenges compared to established methods.

Pharmacology

Pharmacodynamics

Paracetamol exerts its primary therapeutic effects as an and through central mechanisms, with its exact mode of action remaining incompletely elucidated despite extensive research. It is a weak inhibitor of (COX) enzymes, particularly in the , where it reduces (PGE2) synthesis that modulates pain perception and thermoregulation. Unlike non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol demonstrates minimal peripheral COX inhibition in inflamed tissues, likely due to its sensitivity to high concentrations that impair its activity in such environments, explaining its negligible effects. The properties primarily involve selective inhibition of COX-2 or a COX-1 variant (sometimes termed COX-3) in the and , leading to decreased central to nociceptive stimuli without substantially affecting gastrointestinal or platelet COX-1. Additional central pathways include activation of descending serotonergic inhibitory systems and modulation via the metabolite N-arachidonoylphenolamine (AM404), which inhibits fatty acid amide hydrolase, enhances endocannabinoid signaling at CB1 receptors, and activates transient receptor potential vanilloid 1 () channels to elevate pain thresholds. These mechanisms collectively contribute to analgesia without the peripheral suppression seen with NSAIDs. As an , paracetamol acts on the by inhibiting COX-mediated PGE2 production, which disrupts fever-inducing signals from peripheral cytokines, thereby resetting the thermoregulatory set point. This central selectivity is supported by studies showing effective fever reduction at doses that do not significantly alter peripheral markers. Proposed alternative contributors, such as scavenging or indirect effects on and systems, have been hypothesized but lack definitive causal evidence in humans. Overall, while COX inhibition provides a foundational , multifaceted central interactions underscore paracetamol's profile as a non- with targeted efficacy. Paracetamol also modulates emotional and cognitive processing. It dulls emotional pain, reduces the intensity of both negative and positive emotions, and decreases empathy, particularly in response to others' suffering. These effects are typically short-term, arising from single therapeutic doses. They are linked to interactions with serotonergic pathways and endocannabinoid signaling. Additionally, paracetamol may lower risk perception, potentially leading to increased risk-taking behavior, while enhancing reflective thinking.

Pharmacokinetics

Paracetamol is rapidly and nearly completely absorbed from the after , with peak plasma concentrations occurring within 30 to in adults under fasting conditions. is approximately 70-90%, influenced by first-pass hepatic , and absorption may be delayed by food intake. The drug exhibits wide distribution throughout total , with a of about 0.9-1.0 L/kg in adults. is low at therapeutic doses (negligible to 20%), increasing to 10-25% or higher during overdose due to saturation effects. Paracetamol undergoes extensive hepatic , accounting for over 90% of elimination at therapeutic doses. Approximately 50-60% is conjugated with to form paracetamol-glucuronide, 25-35% with to paracetamol-sulfate, 5-15% oxidized by enzymes (primarily ) to the reactive intermediate N-acetyl-p-benzoquinone imine (), and the remainder excreted unchanged. is normally detoxified by conjugation with , but this pathway can become saturated in overdose, leading to . Elimination follows kinetics with a plasma elimination of 1.5-3 hours in healthy adults, though it may extend to 2-4 hours in some populations or with hepatic impairment. Over 90% of metabolites are excreted renally within 24 hours, with less than 5% of the parent drug appearing unchanged in . Total body clearance is approximately 4.5-5.5 mL/kg/min in healthy subjects.

Clinical Uses

Analgesic Applications

Paracetamol is indicated for the management of mild to moderate acute , including tension headaches, dental , musculoskeletal strains, postoperative discomfort following minor procedures, and dysmenorrhea. For menstrual pain (dysmenorrhea), while paracetamol provides analgesia without anti-inflammatory effects, ibuprofen is generally more effective as an NSAID that reduces prostaglandins and inflammation causing cramps, and is recommended as first-line treatment. Standard oral dosing for adults typically ranges from 500 to 1000 mg every 4 to 6 hours, not exceeding 4000 mg per day, with intravenous formulations reserved for patients unable to tolerate oral intake or requiring rapid onset in settings. In clinical guidelines for acute dental pain, paracetamol serves as a first-line option, often combined with non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen for enhanced efficacy in moderate cases, achieving pain relief in the majority of patients within 30 to when administered at 1000 mg. For postoperative pain, such as after ambulatory surgery, single-dose paracetamol at 1000 mg provides statistically significant but modest reductions in pain intensity compared to , with for one additional patient achieving at least 50% pain relief estimated at 5 to 8. Evidence from systematic reviews supports its application in osteoarthritis of the knee or hip, where regular dosing yields a mean difference in pain reduction of -0.3 points on a 0-10 visual analog scale versus , though this benefit is modest and may not exceed the minimal clinically important difference for all patients. In contrast, applications for chronic show minimal or no clinically relevant efficacy, with meta-analyses reporting no significant difference from in pain scores or function after up to 12 weeks of use at 4000 mg daily. Combinations with or weak opioids extend its utility for breakthrough in these contexts, demonstrating superior relief over monotherapy in randomized trials for acute or tension-type headaches. For headaches, both paracetamol and ibuprofen are effective, with paracetamol often preferred for simple tension headaches, while ibuprofen may be better for inflammatory or tension-type headaches due to its anti-inflammatory action.

Antipyretic Effects

Paracetamol exerts its antipyretic effects primarily through central inhibition of (PGE2) synthesis in the , which lowers the thermoregulatory set point elevated during fever. This action is mediated by weak inhibition of enzymes, particularly a variant of COX-1 or the proposed COX-3 isoform in the brain, rather than peripheral COX-2 as seen with non-steroidal anti-inflammatory drugs (NSAIDs). Clinical trials demonstrate that oral or intravenous paracetamol reliably reduces fever in adults and children with infectious causes, including viral upper respiratory infections such as the common cold and influenza, providing symptomatic relief for associated fever, headache, and muscle pain without treating the underlying viral infection. For children aged 12 weeks and older, dosing is weight-based at 10-15 mg/kg every 4-6 hours, with a maximum daily dose of 60-75 mg/kg, adhering to a maximum of 4-5 doses in 24 hours for safety; in Mexico, for drops (common concentration 100 mg/ml), this equates to 0.1-0.15 ml/kg per dose (e.g., 2 drops ≈ 0.1 ml ≈ 10 mg/kg), while for syrup (e.g., 160 mg/5 ml), calculate the equivalent volume to achieve 10-15 mg/kg; always use the correct measuring device, follow weight-based dosing charts or consult a doctor or prospectus, and do not exceed 60-75 mg/kg/day. This typically lowers body by 1-1.5°C within 1-2 hours after a standard dose, with effects lasting 4-6 hours. A randomized trial of 1 g intravenous paracetamol in adults with -related fever showed rapid onset and sustained reduction compared to baseline, though efficacy depends on hepatic . In critically ill patients with suspected , paracetamol produced a modest mean temperature decrease of 0.3°C over 48 hours without improving outcomes like mortality or ICU stay. Comparisons with alternatives indicate paracetamol is effective but sometimes less potent than ibuprofen for fever reduction, particularly in children under 2 years, where ibuprofen achieves greater temperature drops at 4-24 hours post-dose. High-dose paracetamol (20-30 mg/kg) outperforms standard dosing in speed and duration against agents like in febrile children, though combinations with ibuprofen enhance overall without increased adverse events. Evidence supporting routine antipyretic use for fever alone is limited and inconsistent, especially in children, with systematic reviews finding weak support for paracetamol over in reducing without clear benefits to discomfort, illness duration, or recovery. Meta-analyses in febrile adults show no reduction in mortality risk from fever therapy (risk ratio 1.04), suggesting interventions like paracetamol primarily alleviate symptoms rather than alter disease course, as fever may confer adaptive benefits in host defense. Guidelines thus prioritize its use for comfort in symptomatic patients over normative control, with authoritative sources such as the NHS recommending paracetamol for treating high temperature (fever) in adults and children, the Mayo Clinic noting acetaminophen as a standard option to reduce fever and associated discomfort, and the WHO recommending it for managing fever in conditions like dengue and chikungunya, emphasizing that it does not address underlying .

Other Therapeutic Indications

Intravenous or oral paracetamol has emerged as an alternative therapy for closing hemodynamically significant (PDA) in preterm neonates, particularly when nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or indomethacin are contraindicated due to risks like renal impairment or . A 2022 Cochrane of 20 randomized controlled trials involving over 1,400 preterm infants found that paracetamol achieves PDA closure rates of approximately 75% after one or two courses, comparable to ibuprofen ( 0.90, 95% CI 0.82-0.98), with lower rates of and no significant increase in other adverse events like . Typical regimens involve 15 mg/kg every 6 hours for 3-7 days, with efficacy potentially dose-dependent and higher in infants beyond 28 weeks . However, evidence quality is moderate due to small sample sizes and heterogeneity, and long-term neurodevelopmental outcomes remain understudied, with one 2023 analysis showing no increased mortality risk but calling for further randomized data. In (OA) of the or , paracetamol is frequently prescribed as first-line treatment for , with doses up to 4 g daily. Yet, a 2019 Cochrane review of 10 high-quality trials with 3,541 participants demonstrated only minimal reduction (mean difference -0.49 cm on a 10 cm visual analog scale, 95% CI -0.99 to 0.01) and negligible functional improvements compared to , falling below thresholds (e.g., 9 mm pain reduction or 10% relative change). This aligns with broader overviews indicating paracetamol's (0.18-0.21) is small and often outweighed by risks in chronic use, leading some guidelines to de-emphasize it in favor of non-pharmacological or alternative analgesics. For , systematic reviews, including a Cochrane analysis of three small trials (n=135), found no reliable evidence supporting paracetamol's efficacy either as monotherapy or adjunct to , with no significant differences in pain scores or opioid requirements. Similarly, it shows no benefit for acute or dental pain beyond in high-quality syntheses. Emerging off-label explorations, such as neuroprotective effects or adjunctive roles in chemotherapy-induced symptoms, lack robust support and remain speculative. Overall, indications beyond general analgesia and antipyresis are limited, with PDA closure representing the most evidence-based non-pain application.

Efficacy and Limitations

Evidence for Effectiveness

Paracetamol demonstrates efficacy as an for mild to moderate acute , with systematic reviews of randomized controlled trials (RCTs) indicating that a single oral dose of 1 g provides clinically meaningful relief for approximately 50% of patients, lasting about 4 hours, outperforming but with a number needed to treat (NNT) of around 4 for at least 50% reduction. In postoperative settings, intravenous paracetamol similarly yields effective analgesia for 4 hours post-administration, supported by high-quality evidence from meta-analyses of RCTs in adults and children. For specific acute pains such as dental or postpartum discomfort, doses of 500–1000 mg reduce intensity significantly versus , as evidenced by overviews of multiple RCTs aggregating data from hundreds of patients per condition. Regular consumption of paracetamol does not lead to the development of tolerance to its analgesic effects, unlike some other medications such as opioids. As an , paracetamol lowers elevated body in febrile patients, with meta-analyses of RCTs in children showing statistically significant reductions in fever compared to , though resolution rates may be modestly lower than with ibuprofen (pooled 0.91 favoring ibuprofen). In critically ill adults with suspected , a 1 g dose every 6 hours reduced by about 0.4°C more than over 48 hours, confirming a modest but reliable antipyretic effect without impacting mortality or ICU stay duration. Pediatric studies, including RCTs for post-vaccination fever, further support its role in alleviating fever and associated fussiness, with benefits observable within 1–4 hours. Evidence from combination therapies reinforces paracetamol's utility; for instance, adding (60 mg) to paracetamol enhances relief beyond paracetamol alone in acute settings, as shown in Cochrane-reviewed trials with low rates. Intravenous formulations provide rapid onset (within 5–10 minutes) for acute in surgical or emergency contexts, with RCTs demonstrating reduced requirements when used adjunctively. Overall, these findings from gold-standard sources like Cochrane systematic reviews establish paracetamol as a first-line option for symptomatic relief in non-severe cases, with efficacy grounded in dose-dependent inhibition of central synthesis contributing to its mechanism.

Conditions with Weak or No Benefit

The term "paracetamol paradox" has been used to describe the differences in efficacy between acute and chronic pain conditions, with paracetamol showing greater effectiveness in acute pain but limited benefits in chronic states. Paracetamol demonstrates no clinically meaningful benefit in treating . High-quality evidence from randomized placebo-controlled trials indicates it fails to reduce pain intensity (mean difference -0.5 points on a 0-10 scale, 95% CI -2.9 to 1.9), (mean difference 0.4 points, 95% CI -1.7 to 2.5), or improve compared to . An overview of systematic reviews corroborates this, reporting high-quality evidence of ineffectiveness for acute specifically (mean difference 0.2 points on a 0-10 scale, 95% CI -0.1 to 0.4). These findings, derived from meta-analyses of over 3,500 participants across multiple trials, have prompted recommendations to reconsider its routine inclusion in clinical guidelines for this condition. In osteoarthritis, particularly of the hip or knee, paracetamol offers only minimal short-term relief that does not meet thresholds. A of randomized trials showed a small reduction in scores (-3.7 mm on a 100 mm , 95% CI -5.5 to -1.9) and disability (-2.9 points, 95% CI -4.9 to -0.9), but these effects are deemed negligible and insufficient to justify routine first-line use given its limited efficacy relative to alternatives like NSAIDs, despite recommendations in some guidelines as an initial option for mild-to-moderate pain due to lower gastrointestinal risks. Paracetamol is recommended for arthritis pain without prominent inflammation, often tried first as it is gentler on the stomach than NSAIDs, but it is less effective for osteoarthritis than NSAIDs. Long-term benefits remain unestablished, with no improvements in function or progression of joint disease observed. Evidence also points to weak or absent efficacy in other pain states, including from common colds and certain procedural pains such as those following in children or , though these rely on lower-quality data from fewer trials. Paracetamol does not relieve nasal congestion, as it lacks decongestant effects to reduce nasal swelling or stuffiness; it is effective only for associated fever and pain or discomfort. In children, nasal congestion is best managed with non-medication approaches such as saline nasal drops or sprays, bulb syringe or nasal aspirator to clear mucus, cool-mist humidifiers, and increased fluids. Over-the-counter cough and cold medicines, including multi-symptom products containing decongestants or antihistamines, are generally not recommended for young children due to limited effectiveness and potential risks; consultation with a healthcare provider is advised for children under 6 years old. Paracetamol's mechanism, which lacks substantive effects, further limits its utility in conditions driven by , such as acute gouty , where non-steroidal drugs outperform it in comparative studies. This limitation also applies to other inflammatory joint conditions, including rheumatoid arthritis. Systematic reviews have found weak evidence for the efficacy of paracetamol in inflammatory arthritis, with an additive benefit when combined with NSAIDs but uncertain benefit compared to NSAIDs alone. NSAIDs are generally preferred for pain relief due to their anti-inflammatory properties, and paracetamol is not a reliable alternative when NSAIDs fail to provide adequate relief, though it may offer mild additional benefit as an adjunct to other treatments.

Safety Profile

Common Adverse Effects

Paracetamol is generally well-tolerated at recommended therapeutic doses, with most users experiencing no adverse effects or only mild, transient symptoms comparable to in clinical trials. The most frequently reported common adverse effects include , , loss of appetite, and , occurring in a small percentage of patients during short-term use. Other mild effects such as , increased sweating, and stomach cramps have been noted in post-marketing surveillance and clinical observations. Skin rashes, pruritus, and other reactions represent additional common cutaneous effects, though these are infrequent and typically resolve upon discontinuation. In pediatric populations, occasional reports include drowsiness, , or transient low , but these remain uncommon at standard doses. Overall incidence of these effects is low, with systematic reviews indicating no significant difference from for any or serious adverse events in acute settings, though individual susceptibility varies. In comparison to ibuprofen, paracetamol is generally well-tolerated at therapeutic doses with minimal gastrointestinal or cardiovascular effects, unlike ibuprofen which carries higher risks of gastric irritation, ulcers, bleeding, renal impairment, and cardiovascular events particularly with prolonged use or in at-risk patients (e.g., those with ulcers, heart/kidney disease, or third-trimester pregnancy). Both have low neurological impact at standard doses, though emerging studies suggest possible emotional blunting with paracetamol (controversial) or temporary cerebral anti-inflammatory with ibuprofen, but no significant clinical impact. The main risk for paracetamol remains hepatotoxicity in overdose.

Serious Risks Including Hepatotoxicity

represents the primary serious risk associated with paracetamol, primarily occurring in overdose scenarios where the drug's reactive metabolite, , depletes hepatic stores and binds to cellular proteins, leading to centrilobular . This process is mediated by enzymes, particularly , which generate NAPQI in excess of capacity during high doses. Acute exceeding 150 mg/kg or 12 g in adults poses a high risk of severe liver damage, with developing in approximately 6% of cases where serum concentrations surpass 200 μg/mL at 4 hours post-ingestion. Risk factors amplifying susceptibility include chronic alcohol consumption, which induces and impairs glutathione regeneration; ; underlying ; and repeated supratherapeutic dosing (e.g., 4-6 g/day over days), with high-dose or long-term use (e.g., >1500 mg/day in susceptible individuals) increasing risk of liver dysfunction or fulminant hepatitis. Paracetamol accounts for about 56% of severe acute and cases in regions with available data, often necessitating transplantation or resulting in mortality without prompt intervention like N-acetylcysteine administration. Unintentional overdoses, particularly in those with or preexisting hepatic conditions, contribute disproportionately to incidence. Beyond , other serious adverse effects are infrequent at therapeutic doses but include rare reactions such as Stevens-Johnson syndrome, , shock, and , along with asthma attacks (particularly in aspirin-sensitive patients), interstitial pneumonia, acute kidney injury (which may occur beyond overdose contexts), blood disorders (e.g., , ), and drug hypersensitivity syndrome, with frequency often unknown or very rare. can accompany severe hepatotoxicity in overdose, affecting up to 25% of cases, while chronic high-dose use has been linked to potential renal impairment in some observational studies, though causality remains debated due to confounding factors like underlying conditions. Overall, while therapeutic use carries low risk of serious events, patients should avoid combining paracetamol with other acetaminophen-containing products to prevent unintentional overdose, discontinue use if serious symptoms occur, and seek medical attention; vigilance against cumulative dosing and individual vulnerabilities is essential to mitigate these hazards.

Considerations for Special Populations

In pediatric populations, paracetamol is approved for use in infants from 2-3 months of age, with medical guidance required under 12 weeks; for very young infants under 3 months, such as a 1-month-old typically weighing around 4 kg, paracetamol dosing remains weight-based at 10-15 mg/kg per dose (every 6-8 hours, maximum 60 mg/kg/day), equating to approximately 40-60 mg per dose, and commercial 80 mg suppositories are indicated for children from 3 months of age and are not recommended as a standard dose for younger infants, with rectal administration in neonates potentially involving diluted oral liquid under medical supervision. it reduces fever and pain but has no decongestant effects to relieve nasal congestion, and is generally preferred over ibuprofen for younger infants due to ibuprofen's contraindication under 6 months. The FDA advises against over-the-counter cough and cold products containing decongestants or antihistamines for children under 2 years, with caution recommended for those under 6 years due to limited effectiveness and potential risks; paracetamol is suitable for fever and pain but not for managing nasal congestion, which is best addressed with non-pharmacological methods such as saline nasal drops. Dosing is weight-based to minimize overdose risk, typically 10-15 mg/kg every 4-6 hours, not exceeding 60 mg/kg daily or 4 doses in 24 hours. Overdosing occurs frequently due to non-weight-adjusted administration, with children over 3 years at higher risk of supratherapeutic doses leading to potential . While guidelines endorse its use for fever and , some analyses question its long-term safety in infants based on animal and human data suggesting neurodevelopmental effects, though clinical consensus supports judicious use. For elderly patients, the standard adult dose of 500-1000 mg every 4-6 hours (maximum 4 g daily) applies without routine reduction, but increased susceptibility to adverse effects arises from comorbidities, reduced hepatic function, and . For high-age elderly patients (e.g., 88-year-olds), particularly for fever management, a more conservative dosage of 300-500 mg every 6-8 hours, up to 2-3 times per 24 hours, with a daily total not exceeding 2 g is recommended; further reduce for severe liver or kidney issues. Start with smaller doses (e.g., half tablet) and monitor for sweating or blood pressure changes to avoid collapse. Frail or malnourished older adults may require dose limits of 3 g daily to mitigate risk, particularly with concurrent alcohol use or low body weight. During pregnancy, remains the preferred , but exposure—reported in over 60% of —has been associated in multiple observational studies with increased risks of neurodevelopmental disorders such as autism spectrum disorder, ADHD, and attention issues in offspring, though causality is not established, confounding factors may be involved, and evidence is mixed per recent reviews. The FDA and professional bodies like SMFM advise its use only when necessary for or fever, with ongoing review of chronic exposure risks, especially near term. In Vietnam, Efferalgan (paracetamol) is commonly used for pain and fever relief during pregnancy, with the recommended dosage the same as for non-pregnant adults: 500 mg to 1 g every 4-6 hours as needed, not exceeding 4 g per day, at the lowest effective dose for the shortest duration possible, and only under medical advice or supervision to minimize risks. In , it is compatible with , as levels in milk are low (0.04-0.23% of maternal dose) and no adverse effects are documented; scheduled postpartum dosing may even support initiation. Patients with hepatic impairment face heightened risk due to impaired and sulfation pathways; paracetamol is contraindicated in severe disease and limited to 2 g daily or less in mild cases, with avoidance in active . In renal impairment, no dose adjustment is generally needed for short-term use, as paracetamol is primarily hepatically metabolized, but monitoring for accumulation of metabolites is advised in end-stage disease, and AKI from overdose rarely occurs without hepatic involvement. Paracetamol is suitable for short-term headache relief in patients with diabetes and hypertension during common colds, as it lacks the blood pressure-elevating or renal effects of NSAIDs; single-ingredient formulations should be used at standard adult dosing (500-1000 mg every 4-6 hours, maximum 4000 mg daily), limited to 3-5 days if liver function is normal, avoiding multi-ingredient products containing paracetamol to prevent inadvertent overdose. In patients experiencing acute myocardial infarction, paracetamol is generally safe, with animal studies and reviews indicating no adverse effects on infarct size, hemodynamics, or outcomes. However, it lacks antiplatelet effects and is not recommended as a substitute for aspirin (e.g., chewable 300 mg if not contraindicated) as first aid while awaiting emergency care. No safe amount of paracetamol is recommended when consuming alcohol, with risk heightened in chronic consumers (more than 3 drinks per day) or with high paracetamol doses; some experts suggest not exceeding 2 g/day in such cases, though avoidance is ideal to prevent depletion exacerbating toxicity. In patients who consume alcohol, paracetamol use increases the risk of hepatotoxicity due to CYP2E1 induction and glutathione depletion, potentially leading to acute liver failure, particularly in chronic or heavy drinkers. In comparison, NSAIDs combined with alcohol primarily elevate the risk of gastrointestinal bleeding and ulcers, which, while serious, is generally less immediately life-threatening than severe hepatotoxicity from paracetamol. Thus, for individuals who drink alcohol, NSAIDs may be safer regarding liver effects, though caution is advised due to heightened GI risks.

Overdose and Toxicity

Mechanisms and Clinical Presentation

In therapeutic doses, paracetamol undergoes primarily phase II metabolism via and sulfation, with approximately 5-10% oxidized by enzymes (predominantly ) to the reactive intermediate N-acetyl-p-benzoquinone imine (). is normally detoxified by conjugation with , preventing cellular damage. In overdose, saturation of conjugation pathways shifts metabolism toward , generating excess that depletes hepatic stores within hours. Unbound then covalently binds to sulfhydryl groups on cellular proteins, particularly in centrilobular hepatocytes, initiating , mitochondrial dysfunction, , and activation of inflammatory pathways such as JNK-mediated signaling. This cascade culminates in hepatocellular necrosis, primarily affecting zone 3 of the liver acinus due to higher expression and lower oxygen tension there. High doses can also induce neurotoxicity, with animal studies showing oxidative stress, disruption of the blood-brain barrier, and neuronal apoptosis. Factors exacerbating include induction of (e.g., by chronic alcohol use or ) or reduced synthesis (e.g., ). The clinical presentation of paracetamol overdose evolves in four phases, though not all patients progress uniformly, and symptoms may be absent in massive ingestions until late stages. Phase 1 (0-24 hours post-ingestion) is often characterized by nonspecific gastrointestinal symptoms such as nausea, vomiting, anorexia, and pallor, or may be entirely asymptomatic; vital signs are typically normal, with no initial evidence of hepatotoxicity. Phase 2 (24-72 hours) marks the onset of hepatic injury, featuring right upper quadrant abdominal pain, tender hepatomegaly, and markedly elevated transaminases (AST and ALT often exceeding 1,000 IU/L), alongside rising bilirubin and prothrombin time; metabolic acidosis or hypoglycemia may emerge in severe cases. Phase 3 (72-96 hours) represents the peak of toxicity, with fulminant hepatic failure manifest as jaundice, coagulopathy (INR >3.5), hepatic encephalopathy (confusion to coma), acute kidney injury, pancreatitis, and lactic acidosis; multiorgan failure occurs in approximately 1-2% of untreated severe overdoses, with mortality risk highest here. Phase 4 (>96 hours to weeks) involves either resolution with declining liver enzymes and recovery of synthetic function in survivors or progression to death from cerebral edema, sepsis, or hemorrhage; renal recovery is usual unless ATN develops. Early serum paracetamol levels, acetaminophen-protein adducts, or Rumack-Matthew nomograms guide risk stratification, as clinical signs lag behind biochemical derangements.

Management and Outcomes

Management of paracetamol overdose begins with rapid assessment of the ingestion history, including timing, amount, and co-ingestants, followed by gastrointestinal if presentation occurs within 1 to 4 hours of ingestion. Activated charcoal, administered at a dose of 1 g/kg, can reduce absorption by up to 50% in this window, though its use is not recommended beyond 4 hours due to limited and risk of aspiration. Serum paracetamol levels are then measured at a minimum of 4 hours post-ingestion and plotted on the Rumack-Matthew to stratify risk, with levels above the treatment line indicating need for antidote. The cornerstone of treatment is N-acetylcysteine (NAC), which replenishes to detoxify the toxic N-acetyl-p-benzoquinone imine (). Intravenous NAC is preferred in many guidelines for its faster onset and lower risk compared to , typically given as a of 150 mg/kg over 1 hour, followed by 50 mg/kg over 4 hours and 100 mg/kg over 16 hours, for a total of 300 mg/kg over 21 hours. NAC is most effective when initiated within 8 hours of , preventing in over 95% of cases at that stage, but remains beneficial up to 24 hours or longer in cases of established . Supportive measures include intravenous fluids for hydration, serial monitoring of , international normalized ratio (INR), renal function, and acid-base status, with considered for severe or renal failure. In severe hepatotoxicity, fulfilling —such as arterial pH <7.3 after fluid resuscitation, INR >6.5, or combined >300 µmol/L, grade 3-4, and INR >3.5—indicates poor without , which has a exceeding 80% in eligible candidates. Outcomes are favorable with prompt NAC therapy, yielding hepatotoxicity rates below 5% and mortality under 1% in treated acute single overdoses presenting early. Delayed presentation beyond 12 hours correlates with higher risks of (up to 30-40% in untreated massive ingestions >30 g) and death, though NAC extends the therapeutic window, reducing mortality from historical untreated rates of 20-30% to current figures of approximately 0.5-1% in the , where paracetamol accounts for about 500 annual overdose deaths amid 56,000 emergency visits. Chronic supratherapeutic ingestions pose challenges due to absent applicability, often requiring empirical NAC based on aminotransferase elevations >1000 IU/L, with outcomes varying by total dose and comorbidities like chronic alcohol use, which exacerbate formation.

Epidemiological Impact

Paracetamol overdose exemplifies the paracetamol paradox (or Panadol paradox in the UK), wherein a drug considered one of the safest over-the-counter analgesics and antipyretics is the leading cause of acute liver failure in the UK and other countries due to overdose, which produces excess toxic metabolite NAPQI that depletes glutathione and damages the liver. It represents a significant burden, accounting for approximately 6% of reported poisonings globally where data are available, and is implicated in 56% of cases of severe and . In the United States, it leads to around 56,000 visits, 2,600 hospitalizations, and 500 deaths each year, with single-substance exposures numbering 66,710 in according to poison control data. Of these, 8-31% are unintentional, often stemming from therapeutic misadventures like exceeding recommended doses over time, highlighting gaps in dosing awareness rather than solely suicidal intent. In the , paracetamol is the leading agent in self-poisoning, with 82,000-90,000 presentations annually and 150-250 deaths, alongside 15-20 liver transplants required each year in . Regulatory measures, such as pack size limits introduced in , have reduced overdose deaths by 43%, demonstrating that restricting availability can mitigate impulsive acts without fully eliminating the risk from stockpiled supplies or intentional sourcing. Recent Scottish data from 2020-2023 show sustained high emergency attendances for paracetamol-only overdoses, with admissions stable at around 2,000-3,000 yearly from 2010-2021, underscoring persistent vulnerability in young adults and females. Mortality from treated cases remains low at under 2%, but untreated or delayed presentations elevate risks, with paracetamol causing 7% of poisoning-related fatalities in surveyed regions. Long-term outcomes reveal elevated all-cause mortality post-overdose, linked to hepatic sequelae and comorbidities, emphasizing the need for follow-up care beyond acute management. In , intentional paracetamol overdoses prompted over 22,000 hospital cases from 2004-2017, with stable incidence but variable outcomes tied to antidote access. These patterns reflect paracetamol's widespread over-the-counter availability as a key causal factor, outweighing alternatives like ibuprofen in overdose frequency due to lower barriers.

Drug Interactions

Pharmacokinetic Interactions

Paracetamol undergoes pharmacokinetic interactions mainly affecting its absorption rate via gastric emptying modulation and its hepatic through induction or inhibition. These interactions generally do not produce serious adverse effects at therapeutic doses but may alter plasma concentration profiles. Absorption of orally administered paracetamol is rapid and dependent on gastric emptying. Agents that delay gastric emptying, including , anticholinergics such as propantheline and atropine, and opioids like , prolong the time to peak plasma concentration (T_max) and may reduce peak levels (C_max), though remains largely unchanged. Prokinetic drugs like metoclopramide accelerate gastric emptying, hastening absorption, shortening T_max, and increasing C_max without substantially altering the area under the curve (AUC). Lansoprazole similarly hastens absorption of paracetamol solutions, while can decrease overall absorption. Hepatic metabolism, primarily via , sulfation, and minor CYP2E1-mediated oxidation to N-acetyl-p-benzoquinone imine (), is influenced by certain drugs. Enzyme inducers including , , , and chronic increase activity, accelerating paracetamol clearance and NAPQI formation, which may reduce therapeutic efficacy but heightens risk in overdose. Probenecid inhibits and renal tubular secretion of conjugates, reducing paracetamol clearance by approximately 45% (from 6.23 to 3.42 ml/min/kg) and increasing plasma exposure, potentially necessitating dose reduction. Distribution and excretion interactions are minimal; paracetamol exhibits low protein binding and rapid tissue distribution, with metabolites excreted renally. In renal impairment, parent drug half-life is unaffected, but conjugate accumulation occurs. No confirmed pharmacokinetic interactions significantly alter distribution volume or non-renal excretion. Overall, clinically significant pharmacokinetic interactions with paracetamol are limited at standard doses, with monitoring recommended for concomitant use of inducers or probenecid.

Clinical Significance

Paracetamol exhibits a relatively low potential for clinically significant drug interactions compared to other analgesics, owing to its minimal impact on cytochrome P450 enzymes involved in the metabolism of most drugs. No significant pharmacological interactions have been identified between paracetamol and oral rehydration solutions (e.g., Pedialyte or suero oral), and they are commonly co-administered in cases of fever accompanied by dehydration, though consultation with a healthcare professional is recommended before combining treatments. However, interactions that alter its hepatic metabolism—primarily via induction of CYP2E1, which increases production of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI)—can elevate the risk of hepatotoxicity, particularly in vulnerable patients. Chronic alcohol consumption, for instance, induces CYP2E1 activity, potentially amplifying paracetamol-induced liver injury even at therapeutic doses, though evidence for this effect in non-overdose scenarios remains inconsistent and primarily associative rather than causal from controlled studies. This exemplifies the "paracetamol paradox" in alcohol interactions, where acute alcohol consumption may offer some protection against toxicity by competing with paracetamol for CYP2E1, thereby reducing NAPQI formation, while chronic alcohol use increases the risk through enzyme induction. Similarly, anticonvulsants such as phenytoin and carbamazepine, which induce CYP2E1, have been linked to heightened hepatotoxicity risk, with case reports documenting elevated liver enzymes and clinical incidents in polypharmacy settings. A notable interaction occurs with , where paracetamol doses exceeding 2 g daily can dose-dependently prolong the international normalized ratio (INR), increasing bleeding risk through reductions in K-dependent clotting factors II, VII, IX, and X. This effect, observed as early as day 3 of co-administration, necessitates INR monitoring in anticoagulated patients, especially postoperatively where supratherapeutic INR may precipitate hemorrhage. Paracetamol may also reduce steady-state exposure to by approximately 20% via enhanced , potentially compromising seizure control in epileptic patients, warranting dose adjustments. Overall, while these interactions underscore the need for caution in patients with hepatic impairment, , or , paracetamol's profile supports its use as a safer alternative to nonsteroidal drugs in many scenarios, provided dosing remains below 4 g daily and concomitant risks are assessed.

History

Discovery and Initial Research

Paracetamol, also known as acetaminophen, was first synthesized in 1877 by American chemist at through the reduction of p-nitrophenol with tin in the presence of glacial acetic acid. This chemical preparation yielded the compound as a white crystalline substance, though its potential therapeutic value was not immediately recognized or pursued in medical contexts. Initial pharmacological investigations occurred in the late amid research into derivatives for fever reduction and relief. In 1893, German physiologist Joseph von Mering conducted early clinical evaluations of paracetamol, administering it to patients and reporting its and properties in a publication that compared it to , a related compound derived from similar synthesis pathways. Von Mering noted paracetamol's efficacy but concluded phenacetin was preferable, citing concerns over paracetamol's potential based on limited observations, which later proved unfounded. These trials represented the first documented human use of isolated paracetamol, though they were constrained by impure preparations and a lack of standardized dosing. Subsequent early research remained limited, overshadowed by the rapid adoption of (introduced as Antifebrin following accidental discovery of its effects by Arnold Cahn and Paul Hepp in 1886) and especially aspirin after its synthesis and commercialization by in 1899. Paracetamol was occasionally identified as a urinary of phenacetin in studies around 1893, hinting at its role in the metabolism of these analgesics, but no large-scale trials or mechanistic investigations followed in the ensuing decades. This neglect persisted due to phenacetin's perceived advantages and the absence of patent protection for paracetamol, delaying deeper empirical scrutiny until post-World War II re-evaluations.

Commercialization and Patent Issues

Paracetamol's commercial introduction followed decades of limited interest after its initial synthesis in 1878, gaining traction in the mid-20th century as a safer alternative to aniline-based analgesics like and , which were associated with and renal . In the United States, it first appeared on the market in 1950, initially in combination products, before McNeil Laboratories launched the single-ingredient Tylenol elixir for children in 1955, marking a pivotal step in its widespread adoption as an over-the-counter and . This development was supported by clinical studies in the demonstrating its and lower profile compared to predecessors. The absence of a compound patent for paracetamol stemmed from its public disclosure over 70 years prior to commercialization; synthesized by in 1878 and tested clinically as early as 1893 by Joseph von Mering, it constituted that barred exclusive claims on the molecule itself. This status enabled multiple manufacturers to produce and market generic versions shortly after introduction, fostering rapid global dissemination—such as Panadol in the and in 1956—without legal . Subsequent patents focused on formulations, delivery methods, and combinations rather than the core compound, including extended-release particles patented in 2000, but these did not impede the generic dominance of standard oral paracetamol. Patent disputes have primarily arisen in niche areas, such as intravenous formulations and specific tablet designs, rather than the original oral drug; for instance, legal challenges in the 2010s contested listings for acetaminophen injection processes in regulatory compendia like the FDA's Orange Book, highlighting efforts to extend exclusivity through secondary patents amid generic competition. However, the foundational lack of molecule-specific protection ensured paracetamol's affordability and availability, contributing to its status as one of the most consumed pharmaceuticals worldwide by the 1970s.

Regulatory Evolution

Paracetamol was initially approved for therapeutic use in 1951 under prescription-only status, with widespread adoption following McNeil Laboratories' introduction of Tylenol in 1955. By 1960, the U.S. (FDA) reclassified single-ingredient acetaminophen formulations as over-the-counter (OTC) medications, reflecting confidence in its safety profile at recommended doses. In the , paracetamol gained formal recognition in the in 1963, becoming available OTC shortly thereafter, amid growing evidence of its efficacy as an with fewer gastrointestinal side effects than alternatives like aspirin. Concerns over from overdoses emerged in the and , prompting initial regulatory responses focused on labeling. In the U.S., the FDA mandated warning statements on OTC acetaminophen labels in 1977, advising against exceeding the recommended dose to prevent potential liver damage, following reports of cases. This was expanded in subsequent decades; for instance, in 1998, the FDA proposed capping OTC tablet strengths at 500 mg but ultimately permitted higher doses after industry pushback and limited of broad risk. In the UK, early warnings emphasized overdose risks, but regulatory action intensified due to paracetamol's role in self-poisoning, which accounted for a significant portion of admissions by the 1990s. A pivotal change occurred in the UK in September 1998, when restricted pack sizes to a maximum of 32 tablets (16 g) in pharmacies and 16 tablets (8 g) in non-pharmacy outlets, aimed at curbing impulsive overdoses and suicides. Studies evaluating this measure reported a 43% reduction in paracetamol-related deaths and a 17% drop in admissions for overdoses in the decade following implementation, attributing the effect to reduced access to large quantities. In the U.S., similar pack size limits were debated in 2009 amid rising overdose concerns, but the FDA opted against nationwide restrictions, citing insufficient evidence that they would proportionally reduce suicides given differences in patterns compared to the . Further U.S. refinements addressed combination products and chronic use risks. In 2011, the FDA limited acetaminophen content in prescription combinations to 325 mg per dosage unit and required black-box warnings for , reducing inadvertent overdoses from multi-ingredient drugs. Internationally, variations persist; for example, some European countries like mirrored the UK's 1998 restrictions, while maintains OTC status with dose limits but no universal pack caps, reflecting ongoing debates over balancing accessibility and . Recent developments, such as the FDA's 2024 proposal for OTC labels to warn of severe skin reactions, underscore continued evolution toward enhanced risk communication.

Society and Culture

Nomenclature and Branding

Paracetamol's systematic IUPAC name is N-(4-hydroxyphenyl), reflecting its as a substituted with a phenolic hydroxyl group at the para position. This derives from its origins as a of p-aminophenol acetylated at the atom. The generic name "paracetamol" is a portmanteau of "para-acetylaminophenol," emphasizing the para-substituted on the phenol ring, and was adopted internationally following its synthesis and pharmacological evaluation in the early . In contrast, "acetaminophen" is used primarily in the and , stemming from "N-acetyl-p-aminophenol" or "para-acetamidophenol," a rooted in American pharmaceutical standardization during the drug's commercialization in the . These dual names refer to the identical compound (C₈H₉NO₂) but highlight regional differences in pharmacopeial preferences established by bodies like the United States Adopted Names (USAN) Council for acetaminophen and the (BAN) for paracetamol. Commercially, paracetamol is marketed under various trademarks reflecting its global availability as both branded and generic formulations. In the United States, it is predominantly branded as Tylenol by (a subsidiary), introduced in 1955 as a safer alternative to aspirin for children. Internationally, Panadol, developed by Frederick Stearns & Co. (later Sterling-Winthrop and now under GlaxoSmithKline), became a leading brand in the , , , and other markets starting from the late 1950s. Other notable brands include Calpol for pediatric suspensions in the UK and equivalents like Tempra in parts of , though generic versions dominate due to paracetamol's off-patent status since the 1940s. These brands often emphasize formulations tailored to dosage strengths, such as 500 mg tablets, and combination products with opioids or antihistamines for enhanced analgesia.

Formulations and Global Availability

Paracetamol is formulated in multiple to accommodate various patient needs and administration routes. Common oral preparations include immediate-release tablets and caplets typically containing 325 mg to 1000 mg per unit, extended-release caplets at 650 mg, capsules, chewable tablets, oral disintegrating tablets, effervescent tablets, powders, and liquid suspensions or solutions, often at concentrations like 120 mg/5 mL or 160 mg/5 mL for pediatric use. Rectal suppositories, available in strengths such as 100 mg to 500 mg, provide an alternative for patients unable to take oral medications. Intravenous formulations, administered as infusions over or infusions, are used in clinical settings for rapid effect, with doses up to 1000 mg every 6 hours. Paracetamol enjoys broad global availability as an over-the-counter (OTC) medication in most countries, reflecting its status on the World Health Organization's Model List of , where it is recommended in oral liquid (120-125 mg/5 mL), suppository (100 mg), and tablet (100-500 mg) forms for mild to moderate pain and fever management. In the United States, it is marketed as acetaminophen under brands like Tylenol, available OTC without quantity limits but with FDA-mandated labeling warnings on overdose risks. Internationally, brands such as Panadol predominate in regions like , , and , often in similar OTC formulations. Regulatory variations exist to mitigate overdose risks, particularly from self-poisoning. In , 14 of 21 surveyed countries impose pharmacy pack size limits on OTC paracetamol, ranging from 8 to 30 grams, though non-pharmacy sales may lack such controls. Similar restrictions apply in , where maximum OTC pack sizes are often capped at 10-24 grams, with larger quantities requiring prescription. In contrast, countries like the and permit unrestricted OTC sales, emphasizing consumer education via labeling. High-dose or combination products may necessitate prescriptions in jurisdictions such as the for certain formulations. Overall, paracetamol's accessibility supports its role as a first-line , though pack limits in select regions aim to balance availability with public safety.

Public Health and Policy Debates

Paracetamol overdose represents a significant challenge, accounting for approximately 46% of cases and serving as the leading cause in several countries, primarily due to its widespread availability in over-the-counter formulations. Annually in the , it prompts around 56,000 visits, 2,600 hospitalizations, and 500 deaths, often from unintentional supratherapeutic ingestion across multiple products containing the drug. debates center on mitigating these risks through measures such as enhanced labeling, dose limitations in combination products, and pack size restrictions, weighed against preserving access for therapeutic use in and fever management. In the , legislation enacted in September 1998 capped over-the-counter paracetamol pack sizes at 16 tablets for standard packs and 32 for pharmacist-supervised sales, aimed at curbing self-poisoning suicides. This intervention correlated with a 43% reduction in paracetamol-related deaths and a 61% drop in liver transplant registrations for overdose within four years post-implementation, with long-term data confirming sustained declines in mortality without substantial substitution to alternative poisons. Evaluations attribute these outcomes to limiting immediate access to lethal quantities, though overall overdose incidence persisted due to multi-tablet purchases or prescription sources, prompting ongoing discussions on further tightening controls or improving availability like N-acetylcysteine. Australia implemented pack size reductions effective February 1, 2025, limiting non-pharmacy sales to 16 tablets maximum per pack—down from 20—and pharmacy sales to 50 for acute needs, following decisions in 2023 amid rising overdose hospitalizations (around 225 annually) and 50 deaths. These changes build on evidence from international precedents, emphasizing while addressing accidental overdoses, particularly in households with children or those with liver vulnerabilities. In the United States, the has prioritized warnings and formulation limits over broad pack restrictions, mandating since 2014 that prescription acetaminophen-opioid combinations contain no more than 325 mg per dosage unit, which reduced associated hospitalizations by an estimated 20-30%. Consumer advisories stress not exceeding 4 grams daily and checking labels for hidden sources, yet debates persist on whether educational campaigns suffice against structural risks, with critics advocating European-style pack limits to further curb the 55,000-80,000 annual emergency visits. Empirical data supports regulatory interventions' efficacy in lowering without compromising legitimate use, though implementation varies by jurisdiction balancing individual liberty and population-level .

Research Directions

Emerging Therapeutic Roles

Research into paracetamol's applications beyond analgesia and antipyretia has explored its potential neuroprotective effects, particularly in acute neurological conditions. In critically ill patients with acute ischemic stroke, early administration of paracetamol has been associated with reduced 90-day mortality, potentially through mechanisms involving temperature modulation and mitigation of secondary brain injury, as observed in a analysis of over 1,000 ICU cases where adjusted ratios indicated a benefit (HR 0.72, 95% CI 0.54-0.96). Similarly, preclinical models of lipopolysaccharide-induced and d-galactose-induced aging have demonstrated paracetamol's attenuation of and via downregulation of pro-inflammatory cytokines like TNF-α and IL-1β, alongside preservation of synaptic proteins such as BDNF, suggesting a role in countering cognitive decline. These findings, however, stem largely from and observational data, with limited randomized clinical trials confirming or optimal dosing. High-dose paracetamol regimens, often combined with N-acetylcysteine to prevent , have shown preliminary antitumor activity in phase I trials for advanced solid malignancies. In a study of patients with cancers, intravenous doses up to 1,000 mg/kg over 6 hours induced tumor regression in select cases, attributed to selective re-polarization of tumor-associated myeloid cells from pro-tumor M2-like to anti-tumor M1-like phenotypes, without significant off-target effects when rescued with NAC. Conversely, concurrent low-dose use has been linked to diminished efficacy of inhibitors in non-small cell cohorts, possibly via suppression of T-cell activation and production, as evidenced by propensity score-matched analyses showing poorer (HR 1.45, 95% CI 1.12-1.88). These conflicting immunomodulatory effects highlight the need for prospective trials to delineate context-specific dosing. Emerging evidence also points to low-dose paracetamol's antidepressant-like properties in rodent models of , mediated by enhancement of hippocampal and modulation of the , though human trials remain absent. Cardiovascular investigations, however, reveal no clear benefits and potential risks, including dose-dependent elevations in systolic (≈5 mm Hg at 4 g/day) among hypertensive individuals, underscoring paracetamol's limitations outside established indications. Overall, while mechanistic insights support exploratory roles in and , clinical translation requires rigorous validation to outweigh hepatotoxic liabilities.

Safety and Efficacy Reassessments

A 2015 and of randomized -controlled trials concluded that paracetamol provides no clinically significant benefit for and only minimal short-term relief for of the or , with mean differences in pain scores of less than 0.5 points on a 10-point scale. This finding prompted reassessments of its first-line status, as prior guidelines had recommended it broadly for these conditions despite limited evidence of superiority over . Subsequent overviews in 2021 confirmed modest effects for or (mean difference -0.3 points; 95% CI -0.6 to -0.1) but high-quality evidence of ineffectiveness for acute . These analyses highlight paracetamol's weak profile for chronic musculoskeletal pain, questioning its routine use without adjunct therapies. Safety concerns have intensified beyond acute overdose hepatotoxicity, which remains the primary risk, accounting for 56% of severe acute liver injury cases and involving doses exceeding 150 mg/kg or 12 g in adults, with up to 30% mortality without transplantation. Recent observational data link regular long-term use (e.g., 4 g daily) to elevated systolic (≈5 mm Hg increase) in hypertensive individuals, correlating with heightened risks of cardiovascular events like heart attack, stroke, or (from 4.6% baseline). Dose-response patterns in follow-up studies reinforce this association, independent of sodium-containing formulations. Epidemiological studies also report associations between paracetamol exposure—particularly or infancy—and increased risk or exacerbations, with population-attributable risks of 22-38% for symptoms in children, though causation remains debated due to factors like reverse in non-experimental designs. A 2021 review found modest links to future development from prenatal exposure but inconsistent infancy effects. Systematic literature syntheses on long-term harms underscore these patterns, urging caution in vulnerable populations despite paracetamol's overall favorable acute profile when dosed correctly. Reassessments advocate weighing these risks against marginal benefits, favoring alternatives like NSAIDs where contraindicated risks (e.g., gastrointestinal) are managed.

Veterinary Use

Applications in Animals

Paracetamol is employed in primarily as an and agent in certain species, notably dogs and , where it provides mild to moderate pain relief for conditions such as , post-operative discomfort, and fever. In dogs, typical oral dosages range from 10–15 mg/kg every 8 hours for short-term use (up to 5 days), with lower doses (10 mg/kg every 12 hours) considered for longer-term to minimize risks like . Its use has gained acceptance among UK veterinarians, with surveys indicating a shift toward viewing it as a viable adjunct to other analgesics, though often combined with opioids or NSAIDs for enhanced efficacy. In , paracetamol has demonstrated utility for managing laminitis-associated , with a dosage of 10 mg/kg reducing lameness scores without inducing detectable liver damage in controlled studies. Intravenous formulations are explored in dogs for perioperative analgesia as an NSAID alternative, particularly in patients with contraindications to anti-inflammatories, though clinical remains limited and primarily supportive rather than definitive. Applications extend to monitoring contexts, where residues have been detected in tissues of veal calves and urine, reflecting occasional therapeutic or inadvertent exposure rather than routine dosing. Use is contraindicated in cats and ferrets due to their deficient glucuronyl activity, which impairs safe metabolism and predisposes to severe and oxidative damage even at low doses; accordingly, paracetamol is never recommended for these species in clinical practice. In dogs, while generally tolerated at therapeutic levels, monitoring for dose-dependent effects such as vomiting, depression, or elevated liver enzymes is advised, underscoring its role as a secondary rather than first-line option.

Species-Specific Toxicity

Paracetamol exhibits marked species-specific toxicity primarily due to variations in hepatic metabolism, particularly the conjugation pathways for glucuronidation and sulfation, which detoxify the parent compound and prevent accumulation of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). In species with deficient glucuronyl transferase activity, such as cats, sulfation pathways saturate at low doses, depleting glutathione stores and leading to oxidative damage, methemoglobinemia, and Heinz body anemia. Dogs, with more robust glucuronidation, experience primarily hepatotoxicity at higher doses, while other species like birds, ferrets, and snakes demonstrate extreme sensitivity through distinct mechanisms. Cats (Felis catus) are particularly vulnerable, with toxicity occurring at doses as low as 10 mg/kg orally, and severe effects including , facial , and hepatic manifesting within 24-48 hours. Their low levels of high-affinity UDP-glucuronosyltransferase (UGT) enzymes result in minimal (less than 5% of ), forcing reliance on limited sulfation, which rapidly overwhelms at therapeutic human-equivalent exposures. predominates early, with levels exceeding 50% in acute cases, often requiring therapy; untreated mortality approaches 100% at doses over 50 mg/kg. In dogs (Canis lupus familiaris), toxicity thresholds are higher, with safe therapeutic doses up to 15 mg/kg every 12 hours for short-term analgesia, but emerges at 100-150 mg/kg, and lethality at approximately 150 mg/kg due to centrilobular and elevated liver enzymes (ALT/AST >1000 IU/L within 24-72 hours). Unlike cats, dogs metabolize paracetamol via (about 40-50%) and sulfation, reducing NAPQI buildup, though can occur secondarily in susceptible individuals. Facial and paw , vomiting, and are common early signs, with N-acetylcysteine as the to replenish . Breed differences, such as slower clearance in versus Beagles, may influence risk. Other species show variable but often heightened risks: birds, rabbits, ferrets, and pigs develop from single low doses (e.g., <50 mg/kg), manifesting as rapid hepatic failure and due to inefficient conjugation similar to cats. Snakes exhibit extreme sensitivity independent of feline pathways, with phylogenetic origins linked to deficient enzymes, causing lethality at microgram-per-kilogram levels used in baits. In contrast, like rats tolerate higher doses via efficient alternative , though mice and hamsters are more prone to in vitro . Paracetamol is contraindicated in most and equines for similar metabolic limitations, emphasizing the need for species-tailored alternatives in veterinary practice.

References

  1. https://pubmed.ncbi.nlm.nih.gov/18811827/
  2. https://pubmed.ncbi.nlm.nih.gov/34901318/
  3. https://www.acs.org/molecule-of-the-week/archive/a/acetaminophen.html
  4. https://pubmed.ncbi.nlm.nih.gov/11319582/
  5. https://pubmed.ncbi.nlm.nih.gov/26572078/
  6. https://pubmed.ncbi.nlm.nih.gov/23719833/
  7. https://pmc.ncbi.nlm.nih.gov/articles/PMC9125438/
  8. https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.13656
  9. https://emedicine.medscape.com/article/820200-overview
  10. https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen
  11. https://www.ncbi.nlm.nih.gov/books/NBK526213/
  12. https://www.inchem.org/documents/icsc/icsc/eics1330.htm
  13. https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1413658.htm
  14. https://journals.lww.com/cmii/fulltext/2018/16030/history_of_medicine.9.aspx
  15. https://www.tandfonline.com/doi/full/10.1080/23328940.2021.1886392
  16. https://pubs.acs.org/doi/10.1021/acs.jchemed.3c00549
  17. https://www.sciencedirect.com/science/article/pii/S2352554124002043
  18. https://www.farmson.com/blogs/the-science-of-paracetamol-production-unveiling-farmson-pharmaceuticals-precision/
  19. https://patents.google.com/patent/US4954652A/en
  20. https://pubs.acs.org/doi/10.1021/acssuschemeng.4c05353
  21. https://pubmed.ncbi.nlm.nih.gov/15662292/
  22. https://www.ncbi.nlm.nih.gov/books/NBK482369/
  23. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.580289/full
  24. https://pubmed.ncbi.nlm.nih.gov/17884974/
  25. https://pubmed.ncbi.nlm.nih.gov/11113024/
  26. https://onlinelibrary.wiley.com/doi/10.1111/j.1460-9592.2008.02764.x
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC7734311/
  28. https://www.dovepress.com/an-updated-review-on-the-metabolite-am404-mediated-central-mechanism-o-peer-reviewed-fulltext-article-JPR
  29. https://pubmed.ncbi.nlm.nih.gov/16413237/
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC8654482/
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC5015806/
  32. https://www.frontiersin.org/journals/psychology/articles/10.3389/fpsyg.2019.00538/full
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC7511878/
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC6204487/
  35. https://go.drugbank.com/drugs/DB00316
  36. https://pubmed.ncbi.nlm.nih.gov/7039926/
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC6953236/
  38. https://reference.medscape.com/drug/tylenol-acetaminophen-343346
  39. https://www.ncbi.nlm.nih.gov/books/NBK598217/
  40. https://www.ihs.gov/doh/documents/Recommendations%2520for%2520Acute%2520Dental%2520Pain%2520Management.pdf
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC10423591/
  42. https://pubmed.ncbi.nlm.nih.gov/33786837/
  43. https://pmc.ncbi.nlm.nih.gov/articles/PMC4381278/
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC10700436/
  45. https://www.healthychildren.org/English/safety-prevention/at-home/medication-safety/Pages/Acetaminophen-for-Fever-and-Pain.aspx
  46. https://emedicine.medscape.com/article/2172407-overview
  47. https://bnfc.nice.org.uk/drugs/paracetamol/
  48. https://www.nhs.uk/medicines/paracetamol-for-children/
  49. https://www.tempra.com.mx/productos/tempra-solucion-pediatrica-30-ml/
  50. https://www.mayoclinic.org/diseases-conditions/swine-flu/expert-answers/swine-flu-symptoms/faq-20058379
  51. https://pmc.ncbi.nlm.nih.gov/articles/PMC5346867/
  52. https://www.nejm.org/doi/full/10.1056/NEJMoa1508375
  53. https://www.sciencedirect.com/science/article/abs/pii/S073567571730205X
  54. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2772373
  55. https://www.cureus.com/articles/90469-the-antipyretic-effect-of-high-dose-paracetamol-versus-mefenamic-acid-in-the-treatment-of-febrile-children-a-randomized-control-trial
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC10636696/
  57. https://pmc.ncbi.nlm.nih.gov/articles/PMC6532671/
  58. https://www.bmj.com/content/378/bmj-2021-069620
  59. https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-019-1473-z
  60. https://www.nhs.uk/medicines/paracetamol-for-adults/
  61. https://www.mayoclinic.org/diseases-conditions/fever/in-depth/fever/art-20050997
  62. https://www.who.int/news-room/fact-sheets/detail/chikungunya
  63. https://pmc.ncbi.nlm.nih.gov/articles/PMC5554551/
  64. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010061.pub5/full
  65. https://publications.aap.org/neoreviews/article/22/5/e320/180667/Acetaminophen-Therapy-for-Persistent-Patent-Ductus
  66. https://publications.aap.org/pediatrics/article/154/2/e2023065056/197778/Acetaminophen-for-Patent-Ductus-Arteriosus-and
  67. https://pubmed.ncbi.nlm.nih.gov/30801133/
  68. https://www.mja.com.au/journal/2021/214/7/efficacy-and-safety-paracetamol-pain-relief-overview-systematic-reviews
  69. https://ebm.bmj.com/content/25/1/40
  70. https://pmc.ncbi.nlm.nih.gov/articles/PMC6369932/
  71. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2011.00072/full
  72. https://www.cochrane.org/evidence/CD007126_intravenous-paracetamol-acetaminophen-pain-after-surgery-adults-and-children
  73. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822819/
  74. https://www.archivesofmedicalscience.com/Effects-of-acetaminophen-and-ibuprofen-monotherapy-in-febrile-children-a-meta-analysis%2C140875%2C0%2C2.html
  75. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020102
  76. https://www.cochranelibrary.com/doi/10.1002/14651858.CD001547/abstract
  77. https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/j.1875-9114.2011.01085.x
  78. https://www.bmj.com/content/351/bmj.h3705/rr-1
  79. https://www.bmj.com/content/350/bmj.h1225
  80. https://www.hopkinsarthritis.org/arthritis-info/osteoarthritis/oa-treatments/
  81. https://pmc.ncbi.nlm.nih.gov/articles/PMC4365808/
  82. https://www.fda.gov/consumers/consumer-updates/should-you-give-kids-medicine-coughs-and-colds
  83. https://www.fda.gov/drugs/special-features/use-caution-when-giving-cough-and-cold-products-kids
  84. https://pubmed.ncbi.nlm.nih.gov/22942323/
  85. https://www.drugs.com/sfx/paracetamol-side-effects.html
  86. https://www.mayoclinic.org/drugs-supplements/acetaminophen-oral-route-rectal-route/description/drg-20068480
  87. https://adf.org.au/drug-facts/paracetamol/
  88. https://ard.bmj.com/content/75/3/552
  89. https://pmc.ncbi.nlm.nih.gov/articles/PMC6510235/
  90. https://pmc.ncbi.nlm.nih.gov/articles/PMC5489132/
  91. https://pmc.ncbi.nlm.nih.gov/articles/PMC4913076/
  92. https://www.sciencedirect.com/science/article/abs/pii/S0273230015001105
  93. https://www.ncbi.nlm.nih.gov/books/NBK441917/
  94. https://www.cghjournal.org/article/S1542-3565%2808%2900156-0/fulltext
  95. https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2796.2003.01107.x
  96. https://www.tandfonline.com/doi/full/10.1080/17425255.2023.2223959
  97. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-rare-serious-skin-reactions-pain-relieverfever-reducer
  98. https://pmc.ncbi.nlm.nih.gov/articles/PMC7336293/
  99. https://www.medicines.org.uk/emc/product/15384/smpc
  100. https://www.healthychildren.org/English/safety-prevention/at-home/medication-safety/Pages/Ibuprofen-for-Fever-and-Pain.aspx
  101. https://medicalguidelines.msf.org/en/viewport/EssDr/english/paracetamol-acetaminophen-oral-16684400.html
  102. https://pmc.ncbi.nlm.nih.gov/articles/PMC3893958/
  103. https://pmc.ncbi.nlm.nih.gov/articles/PMC9056471/
  104. https://dtb.bmj.com/content/56/6/69
  105. https://www.mayoclinic.org/drugs-supplements/acetaminophen-oral-route-rectal-route/proper-use/drg-20068480
  106. https://www.health.harvard.edu/pain/acetaminophen-safety-be-cautious-but-not-afraid
  107. https://ehjournal.biomedcentral.com/articles/10.1186/s12940-025-01208-0
  108. https://jamanetwork.com/journals/jama/fullarticle/2817406
  109. https://www.fda.gov/news-events/press-announcements/fda-responds-evidence-possible-association-between-autism-and-acetaminophen-use-during-pregnancy
  110. https://www.smfm.org/news/smfm-statement-on-acetaminophen-use-during-pregnancy-and-autism
  111. https://www.ncbi.nlm.nih.gov/books/NBK501194/
  112. https://www.droracle.ai/articles/149495/paracetamol-renal-dose-adjustment
  113. https://www.tandfonline.com/doi/full/10.1080/24734306.2022.2117941
  114. https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/expert-answers/high-blood-pressure/faq-20058281
  115. https://pubmed.ncbi.nlm.nih.gov/15162073/
  116. https://pubmed.ncbi.nlm.nih.gov/16687610/
  117. https://downloads.regulations.gov/FDA-1977-N-0013-0003/attachment_2.doc
  118. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014937/
  119. https://pubmed.ncbi.nlm.nih.gov/10566713/
  120. https://litfl.com/paracetamol-toxicity/
  121. https://derangedphysiology.com/main/required-reading/environmental-injuries-and-toxicology/Chapter-511/paracetamol-toxicity
  122. https://pmc.ncbi.nlm.nih.gov/articles/PMC9144323/
  123. https://pmc.ncbi.nlm.nih.gov/articles/PMC3000821/
  124. https://emedicine.medscape.com/article/820200-clinical
  125. https://emedicine.medscape.com/article/820200-treatment
  126. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808062
  127. https://www.nejm.org/doi/full/10.1056/NEJM198812153192401
  128. https://www.uptodate.com/contents/acetaminophen-paracetamol-poisoning-management-in-adults-and-children
  129. https://pmc.ncbi.nlm.nih.gov/articles/PMC2637612/
  130. https://www.tga.gov.au/news/media-releases/independent-review-paracetamol-overdose
  131. https://www.dynamed.com/condition/acetaminophen-poisoning
  132. https://pmc.ncbi.nlm.nih.gov/articles/PMC4243911/
  133. https://www.ox.ac.uk/news/2013-02-08-smaller-packs-paracetamol-have-reduced-overdose-deaths-43
  134. https://academic.oup.com/jpubhealth/advance-article/doi/10.1093/pubmed/fdaf076/8185595
  135. https://pmc.ncbi.nlm.nih.gov/articles/PMC5759248/
  136. https://www.mja.com.au/journal/2019/211/5/paracetamol-poisoning-related-hospital-admissions-and-deaths-australia-2004-2017
  137. https://academic.oup.com/qjmed/article/95/9/609/1574663
  138. https://pubmed.ncbi.nlm.nih.gov/15662293/
  139. https://pubmed.ncbi.nlm.nih.gov/4694406/
  140. https://www.drugs.com/drug-interactions/atropine-with-paracetamol-280-0-11-2744.html?professional=1
  141. https://www.bmj.com/content/1/5853/587
  142. https://pubmed.ncbi.nlm.nih.gov/10405233/
  143. https://onlinelibrary.wiley.com/doi/10.1155/2020/1354209
  144. https://pmc.ncbi.nlm.nih.gov/articles/PMC4498995/
  145. https://pubmed.ncbi.nlm.nih.gov/8157041/
  146. https://medicinesinformation.co.nz/bulletins/pharmacokinetic-medicines-interactions-with-probenecid/
  147. https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.1980.tb01812.x
  148. https://www.drugs.com/drug-interactions/dextrose-10-and-electrolyte-no-48-with-paracetamol-1499-10199-11-2744.html
  149. https://pubmed.ncbi.nlm.nih.gov/10759684/
  150. https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2125.2000.00167.x
  151. https://pmc.ncbi.nlm.nih.gov/articles/PMC2014937/
  152. https://pmc.ncbi.nlm.nih.gov/articles/PMC6995317/
  153. https://www.singlecare.com/blog/acetaminophen-interactions/
  154. https://pubmed.ncbi.nlm.nih.gov/17145598/
  155. https://www.sciencedirect.com/science/article/pii/S0006497119790429
  156. https://www.droracle.ai/articles/393123/when-to-recheck-inr-after-paracetamol
  157. https://www.sciencedirect.com/science/article/pii/S2352512623004320
  158. https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.12840
  159. https://www.drugs.com/drug-interactions/paracetamol-with-warfarin-11-2744-2311-0.html
  160. https://www.hilarispublisher.com/open-access/history-and-interaction-of-parcetamol-72828.html
  161. https://edu.rsc.org/resources/paracetamol-book-background-information/4018934.article
  162. https://www.reagent.co.uk/blog/paracetamol-history-of-a-pain-reliever/
  163. https://www.linkedin.com/pulse/history-paracetamol-lakshman-iyer-m-pharm-m-m-m-
  164. https://academic.oup.com/book/29853/chapter/252988948
  165. https://www.fda.gov/about-fda/fda-history-exhibits/drug-therapeutics-regulation-us
  166. https://www.thefdalawblog.com/2014/06/a-first-orange-book-patent-delisting-counterclaim-denied-in-litigation-over-acetaminophen-injection/
  167. https://www.uspharmacist.com/article/acetaminophen-intoxication-a-criticalcare-emergency
  168. https://www.propublica.org/article/tylenol-mcneil-fda-use-only-as-directed
  169. https://pmc.ncbi.nlm.nih.gov/articles/PMC3125378/
  170. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2710.2007.00842.x
  171. https://www.bmj.com/content/346/bmj.f403
  172. https://www.fda.gov/drugs/information-drug-class/acetaminophen
  173. https://www.tga.gov.au/resources/guidance/over-counter-otc-medicine-monograph-paracetamol-oral-use
  174. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-agency-initiated-proposed-order-regarding-otc-monograph-drugs-containing-acetaminophen
  175. https://www.chemspider.com/Chemical-Structure.1906.html
  176. https://merckindex.rsc.org/monographs/m1317
  177. https://www.emedicinehealth.com/are_acetaminophen_and_paracetamol_the_same/article_em.htm
  178. https://www.drugs.com/medical-answers/paracetamol-usa-3555654/
  179. https://www.drugs.com/paracetamol.html
  180. https://www.sciencedirect.com/topics/medicine-and-dentistry/paracetamol
  181. https://list.essentialmeds.org/medicines/15
  182. https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2023.02
  183. https://pubmed.ncbi.nlm.nih.gov/29319222/
  184. https://www.antonpottegaard.dk/publications/originalarticles/o121.pdf
  185. https://www.aetnainternational.com/en/health-wellness/destination-guides/expat-guide-to-dubai/medication-dubai.html
  186. https://pmc.ncbi.nlm.nih.gov/articles/PMC5696016/
  187. https://www.fda.gov/consumers/consumer-updates/dont-overuse-acetaminophen
  188. https://pubmed.ncbi.nlm.nih.gov/25200452/
  189. https://pmc.ncbi.nlm.nih.gov/articles/PMC526120/
  190. https://www.tga.gov.au/news/media-releases/tga-makes-final-decision-reduce-paracetamol-pack-sizes
  191. https://insightplus.mja.com.au/2025/2/paracetamol-restrictions-updated-as-self-harm-levels-remain-high/
  192. https://jamanetwork.com/journals/jama/fullarticle/2802061
  193. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-prescription-acetaminophen-products-be-limited-325-mg-dosage-unit
  194. https://www.thelancet.com/article/S0140-6736%2807%2960631-X/fulltext
  195. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1622440/full
  196. https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-016-0781-6
  197. https://pmc.ncbi.nlm.nih.gov/articles/PMC9586893/
  198. https://www.mdpi.com/2673-4389/4/1/7
  199. https://www.sciencedirect.com/science/article/pii/S147655862500034X
  200. https://pmc.ncbi.nlm.nih.gov/articles/PMC10527930/
  201. https://www.sciencedirect.com/science/article/abs/pii/S0166432824002213
  202. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.056015
  203. https://pubmed.ncbi.nlm.nih.gov/37436926/
  204. https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2022/february/regular-paracetamol-use-linked-to-higher-blood-pressure
  205. https://academic.oup.com/eurheartj/article/45/Supplement_1/ehae666.1226/7837786
  206. https://www.thelancet.com/article/S0140-6736%2808%2961445-2/abstract
  207. https://onlinelibrary.wiley.com/doi/10.1111/cea.12410
  208. https://pubmed.ncbi.nlm.nih.gov/34425045/
  209. https://www.sciencedirect.com/science/article/pii/S0003496724019496
  210. https://thescipub.com/abstract/ajavsp.2021.247.262
  211. https://pmc.ncbi.nlm.nih.gov/articles/PMC10029871/
  212. https://www.veterinary-practice.com/article/assessing-the-use-of-iv-paracetamol-as-an-alternative-to-nsaids
  213. https://www.sciencedirect.com/science/article/pii/S0278691524003788
  214. https://www.petmd.com/pet-medication/acetaminophen-tylenol
  215. https://www.fda.gov/animal-veterinary/animal-health-literacy/get-facts-about-pain-relievers-pets
  216. https://www.merckvetmanual.com/pharmacology/inflammation/nonsteroidal-anti-inflammatory-drugs-in-animals
  217. https://pmc.ncbi.nlm.nih.gov/articles/PMC340185/
  218. https://pubmed.ncbi.nlm.nih.gov/9174118/
  219. https://www.msdvetmanual.com/toxicology/toxicoses-from-human-analgesics/toxicoses-from-human-analgesics-in-animals
  220. https://vcahospitals.com/know-your-pet/acetaminophen-toxicity-in-cats
  221. https://www.sciencedirect.com/science/article/abs/pii/0041008X84902667
  222. https://vcahospitals.com/know-your-pet/acetaminophen-toxicity-in-dogs
  223. https://vetsandclinics.com/en/paracetamol-poisoning-in-dogs-clinical-signs-and-consequences
  224. https://thescipub.com/pdf/ajavsp.2021.247.262.pdf
  225. https://www.townecenteranimalhospital.com/acetaminophen-toxicity-cats-dogs/
  226. https://www.sciencedirect.com/science/article/abs/pii/S1532045618301315
  227. https://pubmed.ncbi.nlm.nih.gov/3566800/
Add your contribution
Related Hubs
User Avatar
No comments yet.