4-Aminophenol prepared this way, and related to the commercially available Metol, has been used as a developer in photography by hobbyists. Unfortunately, it has been implicated in the occasional development of restless leg syndrome. Treatment with N-acetylcysteine, methylene blue or both is sometimes effective after the ingestion of small doses of paracetamol. , Paracetamol is metabolized primarily in the liver, into toxic and nontoxic products.  They are more likely to have abnormal liver function tests, but the importance of this is uncertain. 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It is often sold in combination with other medications, such as in many cold medications. The wholesale price in the developing world is less than US$0.01 per dose. Paracetamol, also known as acetaminophen, is a medication used to treat pain and fever. Paracetamol is sometimes combined with phenylephrine hydrochloride.  Additionally, paracetamol does not affect the closure of the fetal ductus arteriosus as NSAIDs can. [medical citation needed], Paracetamol hepatotoxicity is by far the most common cause of acute liver failure in both the United States and the United Kingdom.  NSAIDs, particularly indomethacin and ibuprofen, have also been used, but the evidence for them is also not strong.  The overdose risk may be heightened by frequent consumption of alcohol. 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. NAPQI is primarily responsible for the toxic effects of paracetamol; this constitutes an example of toxication. , 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 and migraine headaches. , In September 2013, an episode of This American Life titled "Use Only as Directed" highlighted deaths from paracetamol overdose. , The efficacy of paracetamol when used in combination with weak opioids (such as codeine) improved for about 50% of people, but with increases in the number experiencing side effects. ", A report prepared by an internal FDA working group describes a history of FDA initiatives designed to educate consumers about the risk of paracetamol overdose and notes that one challenge to the Agency has been "identifying the appropriate message about the relative safety of acetaminophen, especially compared to other OTC pain relievers (e.g., aspirin and other NSAIDs)". The presence of two activating groups also make the benzene ring highly reactive toward electrophilic aromatic substitution. Paracetamol (acetaminophen) undergoes hydrolysis in acidic conditions to produce an amine and a carboxylic acid. [medical citation needed], Untreated paracetamol overdose results in a lengthy, painful illness. The new fast way. In 2011, the U.S. Food and Drug Administration (FDA) launched a public-education program to help consumers avoid overdose, warning: "Acetaminophen can cause serious liver damage if more than directed is used. , Despite its common use, the mechanism of action of paracetamol is not completely understood.  In three papers published in the September 1948 issue of the Journal of Pharmacology and Experimental Therapeutics, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed using more specific methods that paracetamol was the major metabolite of acetanilide in human blood, and established that it was just as efficacious an analgesic as its precursor. " In a 2011 Safety Warning, the FDA immediately required manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury and required that such combinations contain no more than 325 mg of acetaminophen.  It is typically used for mild to moderate pain relief. Hydrolysis of paracetamol (acetaminophen) in acidic solution produces an amine (4-aminophenol) and a carboxylic acid (acetic acid). , In some formulations, paracetamol is combined with the opiate codeine, sometimes referred to as co-codamol (BAN) and Panadeine in Australia. , Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern.  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.  Overshadowed in part by aspirin, introduced into medicine by Heinrich Dreser in 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter "headache mixtures", usually containing phenacetin, an aminopyrine derivative or aspirin, caffeine, and sometimes a barbiturate.