Paracetamol

Paracetamol,Template:Efn or acetaminophen,Template:Efn is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain.<ref name=":2">Template:Cite journal</ref><ref name="pmid19058473" /><ref name="pmid31892511" /> It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol.

Paracetamol relieves pain in both acute mild migraine and episodic tension headache.<ref name="pmid25600718"/><ref name="pmid27306653"/> At a standard dose, paracetamol slightly reduces fever,<ref name="pmid19058473"/><ref name="pmid27992852"/><ref name= "pmid26518691"/> though it is inferior to ibuprofen in that respect<ref name="pmid20150507"/> and the benefits of its use for fever are unclear, particularly in the context of fever of viral origins.<ref name="pmid19058473"/><ref name="pmid12076499">Template:Cite journal</ref><ref name="pmid31116598"/> 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.<ref name="pmid29671521" /><ref name="pmid21181425" /> Paracetamol is effective for post-surgical pain, but is inferior to ibuprofen for this purpose.<ref name="pmid24338830" /> The paracetamol/ibuprofen combination increases the drugs' potency and is superior to either drug alone.<ref name="pmid24338830"/><ref name="pmid23904576"/> The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant.<ref name="pmid31892511"/><ref name=BMJ2015/><ref name="pmid31908149"/> Evidence supporting its use in low back pain, cancer pain, and neuropathic pain is insufficient.<ref name="pmid31892511"/><ref name=BMJ2015/><ref name="pmid28192789"/><ref name=Saragiotto2016/><ref name="pmid28700092"/><ref name="pmid28027389"/>

In the short term, paracetamol is safe and effective when used as directed.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Short term adverse effects are uncommon and similar to ibuprofen,<ref>Template:Cite journal</ref> but paracetamol is typically safer than nonsteroidal anti-inflammatory drugs (NSAIDs) for long-term use.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen.<ref name="pmid31156845">Template:Cite journal</ref><ref name="pmid31073920"/> Chronic consumption of paracetamol may result in a drop in hemoglobin level, indicating possible gastrointestinal bleeding,<ref name="pmid25732175"/> and abnormal liver function tests. The recommended maximum daily dose for an adult is three to four grams.<ref name="BMJ2015" /><ref name="UK2017">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Higher doses may lead to toxicity, including liver failure.<ref name="AHFS2016">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Daly2008">Template:Cite journal</ref><ref name="Hawkins2007">Template:Cite journal</ref><ref name="Larson2005">Template:Cite journal</ref>

Paracetamol was first made in 1878 by Harmon Northrop Morse or possibly in 1852 by Charles Frédéric Gerhardt.<ref>Template:Cite book</ref><ref name="ourarchive.otago.ac.nz">Template:Cite thesis</ref><ref name = "Roy_2011">Template:Cite book</ref> It is the most commonly used medication for pain and fever in both the United States and Europe.<ref>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> Paracetamol is available as a generic medication, with brand names including Tylenol and Panadol among others.<ref>Template:Cite book</ref> In 2022, it was the 114th most commonly prescribed medication in the United States, with more than 5Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Template:TOC limit

Medical uses

Fever

Paracetamol is used for reducing fever.<ref name=":2" /> However, there has been a lack of research on its antipyretic properties, particularly in adults, and thus its benefits are unclear.<ref name="pmid19058473" /> As a result, it has been described as over-prescribed for this application.<ref name="pmid19058473">Template:Cite journal</ref> 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.<ref name="pmid23818046">Template:Cite journal</ref>

For people in critical care, paracetamol decreases body temperature by only 0.2Template:Ndash0.3Template:Nbsp°C more than control interventions and has no effect on their mortality.<ref name="pmid27992852">Template:Cite journal</ref> It did not change the outcome in febrile patients with stroke.<ref name="pmid28289240">Template:Cite journal</ref> The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported.<ref name="pmid27992852"/> 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.<ref name="pmid31000122">Template:Cite journal</ref> Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection.<ref name="pmid31116598">Template:Cite journal</ref>

The efficacy of paracetamol in children with fever is unclear.<ref>Template:Cite journal</ref> Paracetamol should not be used solely to reduce body temperature; however, it may be considered for children with fever who appear distressed.<ref name=NICE>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It does not prevent febrile seizures.<ref name=NICE/><ref name= "pmid33125519">Template:Cite journal</ref> It appears that 0.2Template:Nbsp°C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergencies.<ref name="pmid19058473"/> Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7Template:Nbsp°C.<ref name="pmid26518691">Template:Cite journal</ref> Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis<ref name="pmid28437025">Template:Cite journal</ref>), including children younger than 2 years old,<ref name="pmid33125495">Template:Cite journal</ref> with equivalent safety.<ref name="pmid20150507">Template:Cite journal</ref> Exacerbation of asthma occurs with similar frequency for both medications.<ref name= "pmid32293369">Template:Cite journal</ref> Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended; however, doses may be alternated if required.<ref name= NICE/>

Pain

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.<ref name="pmid17227290">Template:Cite journal</ref> It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient.<ref name="pmid31892511">Template:Cite journal</ref>

Musculoskeletal pain

The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain.<ref name="pmid31892511"/>

It appears to provide only small and not clinically important benefits in osteoarthritis.<ref name="pmid31892511"/><ref name=BMJ2015>Template:Cite journal</ref> 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.<ref name="pmid31908149">Template:Cite journal</ref> 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.<ref name="pmid31908149"/> Essentially the same recommendation was issued by EULAR for hand osteoarthritis.<ref name="pmid30154087">Template:Cite journal</ref> Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only.<ref name="pmid31126594">Template:Cite journal</ref>

Paracetamol is ineffective for acute low back pain.<ref name="pmid31892511"/><ref name="pmid28192789">Template:Cite journal</ref> No randomized clinical trials evaluated its use for chronic or radicular back pain, and the evidence in favor of paracetamol is lacking.<ref name=Saragiotto2016>Template:Cite journal</ref><ref name=BMJ2015/><ref name="pmid28192789"/>

Headaches

Paracetamol is effective for acute migraine:<ref name="pmid25600718">Template:Cite journal</ref> 39% of people experience pain relief at one hour compared with 20% in the control group.<ref>Template:Cite journal</ref> The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a first-line treatment for migraine".<ref name="pmid29671521">Template:Cite journal</ref> Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently.<ref name="pmid27306653">Template:Cite journal</ref> 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.<ref name="pmid25406671">Template:Cite journal</ref> 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".<ref name="pmid21181425">Template:Cite journal</ref>

Dental and other post-surgical pain

Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain.<ref name="pmid32027199">Template:Cite journal</ref> For the relief of such pain, paracetamol is inferior to ibuprofen.<ref name= "pmid24338830">Template:Cite journal</ref> 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.<ref name="pmid32286125">Template:Cite journal</ref> The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone.<ref name="pmid24338830"/><ref name="pmid23904576">Template:Cite journal</ref><ref name="pmid23794268">Template:Cite journal</ref><ref name="pmid30245281">Template:Cite journal</ref> Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations.<ref name="pmid23904576"/>

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%.<ref name="pmid19160199">Template:Cite journal</ref>

Other pain

Paracetamol fails to relieve procedural pain in newborn babies.<ref name="pmid32257982">Template:Cite journal</ref><ref>Template:Cite journal</ref> For perineal pain postpartum paracetamol appears to be less effective than nonsteroidal anti-inflammatory drugs (NSAIDs).<ref name="pmid33427305">Template:Cite journal</ref>

The studies to support or refute the use of paracetamol for cancer pain and neuropathic pain are lacking.<ref name="pmid28700092">Template:Cite journal</ref><ref name="pmid28027389">Template:Cite journal</ref> There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department.<ref>Template:Cite journal</ref> The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain.<ref>Template:Cite journal</ref>

Patent ductus arteriosus

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.<ref name=":0">Template:Cite journal</ref> Its use for extremely low birth weight and gestational age infants however requires further study.<ref name=":0"/>

Adverse effects

Gastrointestinal adverse effects such as nausea and abdominal pain are extremely uncommon, and their frequency is nothing like that of ibuprofen.<ref name="pmid31073920"/> Increase in risk-taking behavior is possible.<ref>Template:Cite journal</ref> 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,<ref name=":1">{{#invoke:citation/CS1|citation |CitationClass=web }} Template:PD-notice</ref> Rechallenge tests and an analysis of American but not French pharmacovigilance databases indicated a risk of these reactions.<ref name=":1" /><ref name="pmid28963996">Template:Cite journal</ref>

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.<ref name="pmid30801133">Template:Cite journal</ref> 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.<ref name="pmid25732175">Template:Cite journal</ref>

Due to the absence of controlled studies, most of the information about the long-term safety of paracetamol comes from observational studies.<ref name="pmid31073920">Template:Cite journal</ref> 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.<ref name="pmid25732175"/><ref name="pmid31073920"/><ref name="pmid23400756">Template:Cite journal</ref> Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer.<ref name="pmid31073920"/> Those who take it regularly at a higher dose (more than 2Template:Ndash3Template:Nbspg daily) are at much higher risk (3.6Template:Ndash3.7 times) of gastrointestinal bleeding and other bleeding events.<ref name= "pmid29863746"/> Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23%<ref name="pmid32172553">Template:Cite journal</ref> and kidney cancer by 28%.<ref name="pmid23400756"/> Paracetamol slightly but significantly increases blood pressure and heart rate.<ref name="pmid31073920"/> A 2022 double-blind, placebo-controlled, crossover study has provided evidence that daily, high-dose use (4 g per day) of paracetamol increases systolic BP.<ref name="pmid35130054">Template:Cite journal</ref>Template:Primary source inline 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.<ref name="pmid29863746">Template:Cite journal</ref>

The association between paracetamol use and asthma in children has been a matter of controversy.<ref name="Lourido2017">Template:Cite journal</ref> However, the most recent research suggests that there is no association,<ref>Template:Cite journal</ref> and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer, ibuprofen.<ref name="pmid32293369"/>

In recommended doses, the side effects of paracetamol are mild to non-existent.<ref name="PM: FBtCP">Template:Cite book</ref> 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.<ref name="TCD">Template:Cite book</ref> Compared to Ibuprofen—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects.<ref>Template:Cite journal</ref> Prolonged daily use may cause kidney or liver damage.<ref name="TCD" /><ref>Template:Cite news</ref> Paracetamol is metabolized by the liver and is hepatotoxic; side effects may be more likely in chronic alcoholics or patients with liver damage.<ref name="PM: FBtCP" /><ref>Template:Cite book</ref>

Until 2010 paracetamol was believed safe in pregnancy however, in a study published in October 2010 it has been linked to infertility in the adult life of the unborn.<ref>Template:Cite journal</ref> Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood. One recent research study showed evidence that paracetamol can ease psychological pain, but more studies are needed to draw a stronger conclusion.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Unlike aspirin, it is safe for children, as paracetamol is not associated with a risk of Reye syndrome in children with viral illnesses.<ref>Template:Cite journal</ref> Chronic users of paracetamol may have a higher risk of developing blood cancer.<ref>Template:Cite journal</ref>

Use in pregnancy

Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or birth defects. However, indications exist of a possible increase in the risk of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy.<ref name="pmid29863746"/>

Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood asthma,<ref>Template:Cite journal</ref><ref name="pmid28237129">Template:Cite journal</ref> but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult.<ref name="pmid29863746"/> Paracetamol, in a small-scale meta-analysis was also associated with a 20Template:Ndash30% increase in autism spectrum disorder, attention deficit hyperactivity disorder, and conduct disorder, with the association being lower in a meta-analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and whether there was potential bias in the findings.<ref name="pmid29863746"/><ref name="pmid29688261">Template:Cite journal</ref><ref name="pmid31664451">Template:Cite journal</ref> There is also an argument that the large number, consistency, and robust designs of the studies provide strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders.<ref name="pmid29341895">Template:Cite journal</ref><ref name="pmid30654621">Template:Cite journal</ref> In animal experiments, paracetamol disrupts fetal testosterone production, and several epidemiological studies linked cryptorchidism with mother's paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association.<ref name="pmid29863746"/>

The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage, and for the shortest time.<ref name="pmid29863746"/><ref name="pmid28986045">Template:Cite journal</ref><ref name="pmid31242344">Template:Cite journal</ref>

In pregnancy, paracetamol and metoclopramide are deemed safe as are NSAIDs until the third trimester.<ref name="Gilmore2011">Template:Cite journal</ref>

Overdose

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Overdose of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams),<ref name=UK2017/> and can cause potentially fatal liver damage.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}Template:PD-notice</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}Template:PD-notice</ref> 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.<ref name=UK2017/> 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.<ref>Template:Cite journal</ref>

Paracetamol toxicity has become the foremost cause of acute liver failure in the United States by 2003,<ref name="Larson2005" /> and Template:As of, paracetamol accounted for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.<ref>Template:Cite journal</ref> As of 2004, paracetamol overdose resulted in more calls to poison control centers in the U.S. than overdose of any other pharmacological substance.<ref name="Lee2004">Template:Cite journal</ref> 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."<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}Template:PD-notice</ref>Template:Needs update

Overdoses are frequently related to high-dose recreational use of prescription opioids, as these opioids are most often combined with paracetamol.<ref>Template:Cite news</ref> The overdose risk may be heightened by frequent consumption of alcohol.<ref name="Lee2017">Template:Cite journal</ref>

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.<ref name="Rumack1975">Template:Cite journal</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="met1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Treatment is aimed at removing the paracetamol from the body and replenishing glutathione.<ref name="met1"/> 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.<ref name="Daly2008"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it.<ref name="met1" /> Kidney failure is also a possible side effect.<ref name="Lee2017" />

Interactions

Prokinetic agents such as metoclopramide accelerate gastric emptying, shorten time (t_max) to paracetamol peak blood plasma concentration (C_max), and increase C_max. Medications slowing gastric emptying such as propantheline and morphine lengthen t_max and decrease C_max.<ref name="pmid4694406">Template:Cite journal</ref><ref name="pmid15662293">Template:Cite journal</ref> 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.<ref name="pmid15662293"/>

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.<ref name="pmid15662293"/> 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.<ref name= "pmid27147854">Template:Cite journal</ref> On the other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%.<ref name="pmid15662293"/>

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.<ref name="pmid15662293"/>

Paracetamol raises plasma concentrations of ethinylestradiol by 22% by inhibiting its sulfation.<ref name="pmid15662293"/> Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week.<ref name="pmid23736105">Template:Cite journal</ref><ref name="pmid21923443">Template:Cite journal</ref><ref name="pmid21191575">Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

Paracetamol appears to exert its effects through two mechanisms: the inhibition of cyclooxygenase (COX) and actions of its metabolite N-arachidonoylphenolamine (AM404).<ref name=Ghanem2016>Template:Cite journal</ref>

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.<ref name="pmid23719833">Template:Cite journal</ref> 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.<ref name=Ghanem2016/><ref name="pmid23719833"/> The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the central nervous system and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding.

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.<ref name=Ghanem2016/><ref name="pmid29238213">Template:Cite journal</ref> It is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase.<ref name=Ghanem2016/> AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor.<ref name=Ghanem2016/> This and other research indicate that the endocannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol.<ref name=Ghanem2016/><ref name="pmid33328986">Template:Cite journal</ref>

In 2018, Suemaru et al. found that, in mice, paracetamol exerts an anticonvulsant effect by activation of the TRPV1 receptors<ref name="Suemaru2018">Template:Cite journal</ref> and a decrease in neuronal excitability by hyperpolarization of neurons.<ref>Template:Cite journal</ref> 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.<ref name="Suemaru2018" />

Pharmacokinetics

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.<ref>Template:Cite journal</ref> 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.<ref name="pmid7039926">Template:Cite journal</ref>

Paracetamol's bioavailability is dose-dependent: it increases from 63% for 500Template:Nbspmg dose to 89% for 1000Template:Nbspmg dose.<ref name="pmid7039926"/> Its plasma terminal elimination half-life is 1.9Template:Ndash2.5 hours,<ref name="pmid7039926"/> and volume of distribution is roughly 50Template:NbspL.<ref name=Graham_2013>Template:Cite journal</ref> Protein binding is negligible, except under the conditions of overdose, when it may reach 15Template:Ndash21%.<ref name="pmid7039926"/> The concentration in serum after a typical dose of paracetamol usually peaks below 30Template:Nbspμg/mL (200Template:Nbspμmol/L).<ref name=rosen/> After 4 hours, the concentration is usually less than 10Template:Nbspμg/mL (66Template:Nbspμmol/L).<ref name=rosen>Template:Cite book</ref>

File:Metabolism of paracetamol.png

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 2Template:Ndash5% of the drug is excreted unchanged in the urine.<ref name="pmid7039926"/> Glucuronidation by UGT1A1 and UGT1A6 accounts for 50Template:Ndash70% of the drug metabolism. Additional 25Template:Ndash35% of paracetamol is converted to sulfate by sulfation enzymes SULT1A1, SULT1A3, and SULT1E1.<ref name="pmid23462933">Template:Cite journal</ref>

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).<ref name="pmid23462933"/> 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.<ref name="pmid23462933"/>

Yet another minor but important direction of metabolism is deacetylation of 1Template:Ndash2% 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.<ref name=Graham_2013/>

Chemistry

Synthesis

Classical methods

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.<ref name = Ullmann/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

File:Classic syntheses of paracetamol.png

Classical methods for the production of paracetamol

Celanese synthesis

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-catalyzed Beckmann rearrangement of the cetoxime to the para-acetylaminophenol product.<ref name = Ullmann>Template:Ullmann</ref><ref>Template:Cite patent</ref>

File:Celanese method for the preparation of paracetamol.png

Celanese method for the preparation of paracetamol

Reactions

File:Парацетамол 9.jpg

Paracetamol crystals (crystallized from an aqueous solution) under a microscope

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.<ref>Template:Cite journal</ref>

History

File:Axelrod.jpg

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.<ref>Template:Cite journal</ref> But its unacceptable toxic effectsTemplate:Emdashthe 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 tissueTemplate:Emdashprompted the search for less toxic aniline derivatives.<ref name=Bertolini2006rev>Template:Cite journal</ref> Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.<ref name="ourarchive.otago.ac.nz"/><ref name="Roy_2011"/>

Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877,<ref>Template:Cite journal</ref><ref name=badmed/> but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans.<ref name=Bertolini2006rev/> In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.<ref>Template:Cite journal</ref> 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.<ref name=drugdiscov>Template:Cite book</ref>

Von Mering's claims remained essentially unchallenged for half a century until two teams of researchers from the United States analyzed the metabolism of acetanilide and phenacetin.<ref name=drugdiscov/> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> This led to a "rediscovery" of paracetamol.<ref name=Bertolini2006rev/>

Paracetamol was first marketed in the United States in 1950 under the name Trigesic, a combination of paracetamol, aspirin, and caffeine.<ref name=badmed/> 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.<ref name=badmed/> The following year, 1952, paracetamol returned to the U.S. market as a prescription drug.<ref name="pmid329728"/> 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.<ref name="pmid799998">Template:Cite journal</ref><ref name="LandauAchilladelis1999">Template:Cite book</ref> 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.<ref name="pmid799998"/><ref name=badmed>Template:Cite book</ref>

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.<ref name=Bertolini2006rev/> Available in the U.S. without a prescription since 1955<ref name="pmid329728">Template:Cite journal</ref> (1960, according to another source<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>), paracetamol has become a common household drug.<ref>Template:Cite news</ref> In 1988, Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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 1000Template:Nbspmg to 650Template:Nbspmg, 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.<ref name="WebMD">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325Template:Nbspmg 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.<ref name="FDA_20110113">Template:Cite press releaseTemplate:PD-notice</ref><ref name="FDA_CDER">{{#invoke:citation/CS1|citation |CitationClass=web }}Template:PD-notice</ref><ref>Template:Cite news</ref><ref name="NYT_Harris">Template:Cite news</ref><ref>Template:Cite press releaseTemplate:PD-notice</ref> Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325Template:Nbspmg per dosage unit.<ref name="FDA_CDER" /><ref name="NYT_Harris" />

In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In September 2013, "Use Only as Directed", an episode of the radio program This American Life<ref>Template:Cite episode</ref> 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"<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Society and culture

File:Read the Label! There are Risks from Taking Too Much Acetaminophen (5323869745).jpg

Awareness poster on acetaminophen abuse as issued by the FDA

Naming

Paracetamol is the Australian Approved Name<ref>Template:Cite book</ref> and British Approved Name<ref name="MacintyreRowbotham2008"/> as well as the international nonproprietary name used by the WHO and in many other countries; acetaminophen is the United States Adopted Name<ref name="MacintyreRowbotham2008"/> and Japanese Accepted Name and also the name generally used in Canada,<ref name="MacintyreRowbotham2008"/> Venezuela, Colombia, and Iran.<ref name= "MacintyreRowbotham2008">Template:Cite book</ref><ref name=INN>Template:Cite journal</ref> Both paracetamol and acetaminophen are contractions of chemical names for the compound. The word "paracetamol" is a shortened form of para-acetylaminophenol,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and was coined by Frederick Stearns & Co in 1956,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The initialism APAP is used by dispensing pharmacists in the United States.<ref>Template:Cite journal</ref>

Available forms

Paracetamol is available in oral, suppository, and intravenous forms.<ref>Template:Cite book</ref> Intravenous paracetamol is sold under the brand name Ofirmev in the United States.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> As of 1 February 2018, medications containing codeine also became prescription-only in Australia.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Paracetamol is also combined with other opioids such as dihydrocodeine,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> referred to as co-dydramol (British Approved Name (BAN)), oxycodone<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> or hydrocodone.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A combination of paracetamol, codeine, and the doxylamine succinate is also available.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Paracetamol is sometimes combined with phenylephrine hydrochloride.<ref name="AtkinsonStanescu2014">Template:Cite journal</ref> Sometimes a third active ingredient, such as ascorbic acid,<ref name="AtkinsonStanescu2014"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> caffeine,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> chlorpheniramine maleate,<ref name="SenyuvaOzden2002">Template:Cite journal</ref> or guaifenesin<ref name="JaninMonnet2014">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> is added to this combination.

{{#invoke:Gallery|gallery}}

Research

Claims that paracetamol is an effective analgesic medication to treat symptoms of COVID-19 were found to be unsubstantiated.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Veterinary use

File:Brown tree snake aerial bait cartridges.jpg

Brown tree snake aerial bait cartridges consisting of dead mice with 80Template:Nbspmg paracetamol tablets

Cats

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).<ref name="CanVetJ2003-Allen">Template:Cite journal</ref> Treatment of the toxicosis with acetylcysteine is recommended.<ref name="Richardson_2000" />

Dogs

Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.<ref name=smallani>Template:Cite book</ref> A paracetamol–codeine product (brand name Pardale-V)<ref name="Pardale">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person.<ref name="Pardale" /> It should be administered to dogs only on veterinary advice and with extreme caution.<ref name="Pardale" />

The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.<ref name="Richardson_2000">Template:Cite journal</ref><ref name="VetHumToxicol1998-Villar">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.<ref name="Richardson_2000"/><ref name=smallani/>

Snakes

Paracetamol is lethal to snakes<ref>Template:Cite journal</ref> and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam.<ref>Template:Cite journal</ref><ref>Template:Cite news</ref> Doses of 80Template:Nbspmg are inserted into dead mice that are scattered by helicopter<ref>Template:Cite magazine</ref> as lethal bait to be consumed by the snakes.

External links

{{#invoke:navbox|navbox

| name = Analgesics
| title = Analgesics (N02A, N02B)
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| state = collapsed

| group1 = Opioids
| list1 = {{#invoke:navbox|navbox|child

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  | list1 =

• Codeine^#
  • +aspirin
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• Morphine^# (+naltrexone)
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  | group2 = Semisynthetic
  | list2 =

• Acetyldihydrocodeine
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• DihydrocodeineTemplate:Nbsp(+paracetamol)
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}}

| group2 = Paracetamol-type
| list2 =

• Acetanilide^‡
• Bucetin^‡
• Butacetin^‡
• Paracetamol (acetaminophen)^#
  • +aspirin/caffeine
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• Parapropamol^‡
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| group3 = NSAIDs
| list3 = {{#invoke:navbox|navbox|child

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  | list1 =

• Benoxaprofen ^‡
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  | group5 = Fenamates
  | list5 =

• Flufenamic acid
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  | group6 = Salicylates
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• Aspirin (acetylsalicylic acid)^# (+paracetamol/caffeine)
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  | group7 = Pyrazolones
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• Aminophenazone^‡
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  | group8 = Others
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• Benzydamine
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}}

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}}

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| list8 =

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