Paracetamol

Paracetamol (/ˌpærəˈsiːtəmɒl/ or /ˌpærəˈsɛtəmɒl/), also known as acetaminophen ⁱ/əˌsiːtəˈmɪnəfɨn/, or APAP, chemically named N-acetyl-p-aminophenol, is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer).^[7][8]Acetaminophen is the name adopted for this pharmacologic agent in the U.S. (USAN) and Japan; paracetamol is approved in a variety of international venues (INN, AAN, BAN, etc.).^[9][10][11] Common trade names in English-speaking markets are Tylenol andPanadol.

Paracetamol is classified as a mild analgesic. It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies. In combination with opioid analgesics, paracetamol can also be used in the management of more severe pain such as post-surgical pain and providing palliative care in advanced cancer patients.^[12] Though paracetamol is used to treat inflammatory pain, it is not generally classified as an NSAID because it exhibits only weak anti-inflammatory activity.

While generally safe for use at recommended doses, even small overdoses can be fatal. Compared to other over-the-counter pain relievers, paracetamol is significantly more toxic in overdose but may be less toxic when used chronically at recommended doses.^[13]Paracetamol is the active metabolite of phenacetin and acetanilide, both once popular as analgesics and antipyretics in their own right.^[14][15] However, unlike phenacetin, acetanilide and their combinations, paracetamol is not considered carcinogenic at therapeutic doses.^[16]

The words acetaminophen (used in the United States,^[10] Canada,^[10] Japan, and Colombia)^[9] and paracetamol (used elsewhere) both come from a chemical name for the compound: para-acetylaminophenol and para-acetylaminophenol. In some contexts, such as on prescription bottles of painkillers that incorporate this medicine, it is simply abbreviated as APAP, for acetyl-para-aminophenol. It is on the WHO Model List of Essential Medicines, a list of the most important medication needed in a basic health system.

Medical uses[edit]

Fever[edit]

Paracetamol is approved for reducing fever in people of all ages.^[18] The World Health Organization (WHO) recommends that paracetamol be used to treat fever in children only if their temperature is greater than 38.5 °C (101.3 °F).^[19] The efficacy of paracetamol by itself in children with fevers has been questioned^[20] and a meta-analysis showed that it is less effective thanibuprofen.^[21]

Pain[edit]

Paracetamol is used for the relief of pains associated with many parts of the body. It has analgesic properties comparable to those ofaspirin, while its anti-inflammatory effects are weaker. It is better tolerated than aspirin in patients in whom excessive gastric acidsecretion or prolongation of bleeding time may be a concern. Available without a prescription since 1959,^[22] it has since become a common household drug.^[23]

Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as the NSAIDs aspirin and ibuprofen, but ibuprofen and paracetamol have similar effects in the treatment of headache. Paracetamol can relieve pain in mild arthritis, but has no effect on the underlying inflammation, redness, and swelling of the joint.^[24]

Regarding comparative efficacy, studies show conflicting results when compared to NSAIDs. A randomised controlled trial of chronic pain from osteoarthritis in adults found similar benefit from paracetamol and ibuprofen.^[25][26]

The efficacy of paracetamol when used in combination with weak opioids (such as codeine) was assessed in data studies in 1996 and 2009,^[27][28] which found improved efficacy for approximately 50% of patients but increases in the number of patients experiencing adverse effects. Combination drugs of paracetamol and strong opioids like morphine reduce the amount of opioid needed and improve analgesic effect.^[29]

The American College of Rheumatology recommends paracetamol as one of several treatment options for patients with arthritis pain of the hip, hand, or knee that is refractory to non-pharmacological interventions such as exercise and weight loss.^[30]

A joint statement of the German, Austrian, and Swiss headache societies and the German Society of Neurology recommends the use of paracetamol in combination with caffeine as one of several first line therapies for treatment of tension or migraine headache.^[31] In the treatment of acute migraine, it is superior to placebo, with 39% of people experiencing pain relief at 1 hour compared to 20% in the control group.^[32]

Based on a systematic review, paracetamol is recommended by the American College of Physicians and the American Pain Society as a first line treatment for low back pain.^[33][34] However a systematic review published by other authors concluded that evidence for its efficacy is lacking.^[35]

The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of common pain conditions including dental pain, postpartum pain, and headache.^[36]

Adverse effects[edit]

In recommended doses and for a limited course of treatment, the side effects of paracetamol are mild to non-existent.^[37]

Liver damage[edit]

Acute overdoses of paracetamol can cause potentially fatal liver damage. According to the US Food and Drug Administration, "Acetaminophen can cause serious liver damage if more than directed is used."^[38] and in 2011 the FDA required manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury^[39] and launched a public education program to help consumers avoid overdose.^[40][41] The risk may be heightened by frequent consumption of alcohol.Paracetamol toxicity 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][45]} According to the FDA, in the United States there were "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25 percent of the emergency department visits, 10 percent of the hospitalizations, and 25 percent of the deaths."^[46]

Paracetamol is metabolised by the liver and is hepatotoxic; side effects are multiplied when combined with alcoholic drinks, and are very likely in chronic alcoholics or patients with liver damage.^[37][47] Some studies have suggested the possibility of a moderately increased risk of upper gastrointestinal complications such as stomach bleeding when high doses are taken chronically.^[48] Kidney damage is seen in rare cases, most commonly in overdose.^[49] The Food and Drug Administration has warned doctors against prescribing paracetamol/narcotic combinations whose dosages exceed 325 mg of paracetamol due to hepatoxicity risks of greater magnitude than the therapeutic benefits conferred.^[50]

Skin reactions[edit]

On August 2, 2013, the U.S. Food and Drug Administration (FDA) issued a new warning about paracetamol. It stated that the drug could cause rare, and possibly fatal, skin reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis. Prescription-strength products will be required to carry a warning label about skin reactions, and the FDA has urged manufacturers to do the same with over-the-counter products.^[51]

Asthma[edit]

There is an association between paracetamol use and asthma but the evidence suggests that this likely reflects confounders^[52] rather than a causal role.^[53] A 2014 review found that among children the association disappeared when respiratory infections were taken into account.^[54]

As of 2014, the American Academy of Pediatrics and the National Institute for Health and Care Excellence (NICE) continue to recommend paracetamol for pain and discomfort in children,^{[55][56][57][58][59][60]} but some experts have recommended that paracetamol use by children with asthma, or at risk for asthma, should be avoided.^[61][62]

Other factors[edit]

In contrast to aspirin, paracetamol does not prevent blood from clotting (it is not an antithrombotic), and thus may be used in patients where failure of blood coagulation is a concern; and it does not cause gastric irritation.^[63] However, paracetamol does not help reduce inflammation, while aspirin does.^[64] Compared to ibuprofen—whose side effects may include diarrhea, vomiting and abdominal pain—paracetamol has fewer adverse gastrointestinal effects.^[65]

Unlike aspirin, paracetamol is generally considered safe for children, as it is not associated with a risk of Reye's syndrome in children with viral illnesses.^[66]

Paracetamol when taken recreationally with opioids may cause hearing loss.^{[67][better source needed]}

Overdose[edit]

Main article: Paracetamol toxicity

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.^[68] 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.^[69] The process of dying from an overdose usually takes three to five days.

Paracetamol hepatotoxicity is, by far, the most common cause of acute liver failure in both the United States and the United Kingdom.^[45][70] Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance.^[71] Toxicity of paracetamol is believed to be due to its quinone metabolite.^[72]

Untreated overdose can lead to liver failure and death within days. Treatment is aimed at removing the paracetamol from the body and replacing glutathione.^[72] Activated charcoal can be used to decrease absorption of paracetamol if the patient presents for treatment 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 transplantis often required if damage to the liver becomes severe.^[42][73] NAC was usually given following a treatment nomogram (one for patients 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.^[74] NAC also helps in neutralizing the imidoquinone metabolite of paracetamol.^[72] Renal failure is also a possible side effect.

There were tablets available until 2004 (brand-name in the UK Paradote) that combined paracetamol with an antidote (methionine), to protect the liver in case of an overdose. One theoretical, but rarely if ever used, option in the United States is to request a compounding pharmacy to make a similar drug mix for at-risk patients.

In June 2009, a U.S. Food and Drug Administration (FDA) advisory committee recommended that new restrictions should be placed on paracetamol usage in the United States to help protect people from the potential toxic effects. The maximum dosage at any given time would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and narcotic analgesics would be prohibited. Committee members were particularly concerned by the fact that the present maximum dosages of paracetamol had been shown to produce alterations in hepatic function.^[75]

In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit the amount of paracetamol 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.^{[76][77][78][79]} Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.^[77][79] In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.^[80]

Pregnancy[edit]

Experimental studies in animals and cohort studies in humans indicate no detectable increase in congenital malformations associated with paracetamol use during pregnancy.^[81]Additionally, paracetamol does not affect the closure of the fetal ductus arteriosus as NSAIDs can.^[82] However, paracetamol use by mother during pregnancy is associated with an increased risk of childhood asthma.