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Paracetamol
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<h2 id="medical-uses">Medical uses</h2> <h3>Fever</h3> <p>Paracetamol is used for reducing fever.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> However, there has been a lack of research on its <a href="/facts/Antipyretic/lBVzyUFN">antipyretic</a> properties, particularly in adults, and thus its benefits are unclear.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> As a result, it has been described as <a href="/facts/Overmedication/GEmjtKj6">over-prescribed</a> for this application.<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> In addition, low-quality <a href="/facts/Randomized_clinical_trial/LG9lkyVx">clinical data</a> indicates that when used for the <a href="/facts/Common_cold/fP9A03U9">common cold</a>, paracetamol may relieve a <a href="/facts/Nasal_congestion/xClWzxrg">stuffed</a> or <a href="/facts/Rhinorrhea/DJxxlKqs">runny</a> nose, but not other cold symptoms such as <a href="/facts/Sore_throat/00WHEyla">sore throat</a>, <a href="/facts/Malaise/vdb5DxAU">malaise</a>, <a href="/facts/Sneezing/Nxj3dJbc">sneezing</a>, or <a href="/facts/Cough/mqyhR6zj">cough</a>.<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> </p><p>For people in <a href="/facts/Critical_care_medicine/lbc92jbH">critical care</a>, paracetamol decreases body temperature by only 0.2–0.3 °C more than control interventions and has no effect on their <a href="/facts/Mortality_rate/s4gmxyFV">mortality</a>.<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> It did not change the outcome in febrile patients with stroke.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported.<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> Paracetamol offered no benefit in the treatment of <a href="/facts/Dengue_fever/Stn1FvlF">dengue fever</a> and was accompanied by a higher rate of liver enzyme elevation: a sign of potential liver damage.<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection.<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> </p><p>The efficacy of paracetamol in children with fever is unclear.<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a> Paracetamol should not be used solely to reduce body temperature; however, it may be considered for children with fever who appear distressed.<a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a> It does not prevent <a href="/facts/Febrile_seizures/KTMYwpBo">febrile seizures</a>.<a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a><a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a> 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.<a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a> Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7 °C.<a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a> Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis<a class="footnote-ref" id="fnref:64" href="#fn:64"><sup>64</sup></a>), including children younger than 2 years old,<a class="footnote-ref" id="fnref:65" href="#fn:65"><sup>65</sup></a> with equivalent safety.<a class="footnote-ref" id="fnref:66" href="#fn:66"><sup>66</sup></a> <a href="/facts/Exacerbation/krPs4sue">Exacerbation</a> of asthma occurs with similar frequency for both medications.<a class="footnote-ref" id="fnref:67" href="#fn:67"><sup>67</sup></a> Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended; however, doses may be alternated if required.<a class="footnote-ref" id="fnref:68" href="#fn:68"><sup>68</sup></a> </p> <h3>Pain</h3> <p>Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, toothache as well as pain caused by cold, flu, sprains, and <a href="/facts/Dysmenorrhea/WFNGwoY9">dysmenorrhea</a>.<a class="footnote-ref" id="fnref:69" href="#fn:69"><sup>69</sup></a> It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient.<a class="footnote-ref" id="fnref:70" href="#fn:70"><sup>70</sup></a> </p> <h4>Musculoskeletal pain</h4> <p>The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain.<a class="footnote-ref" id="fnref:71" href="#fn:71"><sup>71</sup></a> </p><p>It appears to provide only small and not clinically important benefits in <a href="/facts/Osteoarthritis/Iy1wDA1B">osteoarthritis</a>.<a class="footnote-ref" id="fnref:72" href="#fn:72"><sup>72</sup></a><a class="footnote-ref" id="fnref:73" href="#fn:73"><sup>73</sup></a> <a href="/facts/American_College_of_Rheumatology/jmQexwYg">American College of Rheumatology</a> and <a href="/facts/Arthritis_Foundation/T4Dbu6ye">Arthritis Foundation</a> guideline for the management of osteoarthritis notes that the <a href="/facts/Effect_size/mIpNrPte">effect size</a> in <a href="/facts/Clinical_trial/q8LMr832">clinical trials</a> of paracetamol has been very small, which suggests that for most individuals it is ineffective.<a class="footnote-ref" id="fnref:74" href="#fn:74"><sup>74</sup></a> 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.<a class="footnote-ref" id="fnref:75" href="#fn:75"><sup>75</sup></a> Essentially the same recommendation was issued by <a href="/facts/European_League_Against_Rheumatism/NDhq7yvP">EULAR</a> for hand osteoarthritis.<a class="footnote-ref" id="fnref:76" href="#fn:76"><sup>76</sup></a> Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only.<a class="footnote-ref" id="fnref:77" href="#fn:77"><sup>77</sup></a> </p><p>Paracetamol is ineffective for acute low back pain.<a class="footnote-ref" id="fnref:78" href="#fn:78"><sup>78</sup></a><a class="footnote-ref" id="fnref:79" href="#fn:79"><sup>79</sup></a> No randomized clinical trials evaluated its use for chronic or <a href="/facts/Radicular_pain/EEobDSY3">radicular</a> back pain, and the evidence in favor of paracetamol is lacking.<a class="footnote-ref" id="fnref:80" href="#fn:80"><sup>80</sup></a><a class="footnote-ref" id="fnref:81" href="#fn:81"><sup>81</sup></a><a class="footnote-ref" id="fnref:82" href="#fn:82"><sup>82</sup></a> </p> <h4>Headaches</h4> <p>Paracetamol is effective for acute migraine:<a class="footnote-ref" id="fnref:83" href="#fn:83"><sup>83</sup></a> 39 % of people experience pain relief at one hour compared with 20 % in the control group.<a class="footnote-ref" id="fnref:84" href="#fn:84"><sup>84</sup></a> The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a <a href="/facts/Therapy/2ytkGbgT">first-line treatment</a> for migraine".<a class="footnote-ref" id="fnref:85" href="#fn:85"><sup>85</sup></a> Paracetamol on its own only slightly alleviates episodic <a href="/facts/Tension_headache/Qa0K9IpX">tension headache</a> in those who have them frequently.<a class="footnote-ref" id="fnref:86" href="#fn:86"><sup>86</sup></a> 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.<a class="footnote-ref" id="fnref:87" href="#fn:87"><sup>87</sup></a> 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".<a class="footnote-ref" id="fnref:88" href="#fn:88"><sup>88</sup></a> </p> <h4>Dental and other post-surgical pain</h4> <p>Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain.<a class="footnote-ref" id="fnref:89" href="#fn:89"><sup>89</sup></a> For the relief of such pain, paracetamol is inferior to ibuprofen.<a class="footnote-ref" id="fnref:90" href="#fn:90"><sup>90</sup></a> Full therapeutic doses of nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, <a href="/facts/Naproxen/2oJdSCWq">naproxen</a> or <a href="/facts/Diclofenac/JwjJ8fcP">diclofenac</a> are clearly more efficacious than the paracetamol/codeine combination which is frequently prescribed for dental pain.<a class="footnote-ref" id="fnref:91" href="#fn:91"><sup>91</sup></a> The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone.<a class="footnote-ref" id="fnref:92" href="#fn:92"><sup>92</sup></a><a class="footnote-ref" id="fnref:93" href="#fn:93"><sup>93</sup></a><a class="footnote-ref" id="fnref:94" href="#fn:94"><sup>94</sup></a><a class="footnote-ref" id="fnref:95" href="#fn:95"><sup>95</sup></a> Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations.<a class="footnote-ref" id="fnref:96" href="#fn:96"><sup>96</sup></a> </p><p>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 %.<a class="footnote-ref" id="fnref:97" href="#fn:97"><sup>97</sup></a> </p> <h4>Other pain</h4> <p>Paracetamol fails to relieve procedural pain in <a href="/facts/Newborn_babies/gaEL1QL4">newborn babies</a>.<a class="footnote-ref" id="fnref:98" href="#fn:98"><sup>98</sup></a><a class="footnote-ref" id="fnref:99" href="#fn:99"><sup>99</sup></a> For <a href="/facts/Perineum/MaBAap96">perineal</a> pain <a href="/facts/Postpartum_period/abLj2JtY">postpartum</a> paracetamol appears to be less effective than <a href="/facts/Nonsteroidal_anti-inflammatory_drug/coIkzl4s">nonsteroidal anti-inflammatory drugs</a> (NSAIDs).<a class="footnote-ref" id="fnref:100" href="#fn:100"><sup>100</sup></a> </p><p>The studies to support or refute the use of paracetamol for cancer pain and neuropathic pain are lacking.<a class="footnote-ref" id="fnref:101" href="#fn:101"><sup>101</sup></a><a class="footnote-ref" id="fnref:102" href="#fn:102"><sup>102</sup></a> There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department.<a class="footnote-ref" id="fnref:103" href="#fn:103"><sup>103</sup></a> The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain.<a class="footnote-ref" id="fnref:104" href="#fn:104"><sup>104</sup></a> </p> <h3>Patent ductus arteriosus</h3> <p>Paracetamol helps ductal closure in <a href="/facts/Patent_ductus_arteriosus/cPmKMY6D">patent ductus arteriosus</a>. It is as effective for this purpose as ibuprofen or <a href="/facts/Indomethacin/76bAEl5x">indomethacin</a>, but results in less frequent gastrointestinal bleeding than ibuprofen.<a class="footnote-ref" id="fnref:105" href="#fn:105"><sup>105</sup></a> Its use for extremely low birth weight and gestational age infants however requires further study.<a class="footnote-ref" id="fnref:106" href="#fn:106"><sup>106</sup></a> </p> <h2 id="adverse-effects">Adverse effects</h2> <p>Gastrointestinal adverse effects such as nausea and <a href="/facts/Abdominal_pain/aF6gPB0G">abdominal pain</a> are extremely uncommon, and their frequency is nothing like that of ibuprofen.<a class="footnote-ref" id="fnref:107" href="#fn:107"><sup>107</sup></a> Increase in risk-taking behavior is possible.<a class="footnote-ref" id="fnref:108" href="#fn:108"><sup>108</sup></a> According to the U.S. <a href="/facts/Food_and_Drug_Administration/rCEnh9WB">Food and Drug Administration</a> (FDA), the drug may cause rare and possibly fatal skin reactions such as <a href="/facts/Stevens%E2%80%93Johnson_syndrome/Lx6k5dmJ">Stevens–Johnson syndrome</a> and <a href="/facts/Toxic_epidermal_necrolysis/An3EuYsA">toxic epidermal necrolysis</a>,<a class="footnote-ref" id="fnref:109" href="#fn:109"><sup>109</sup></a> <a href="/facts/Rechallenge/fW3BzkKk">Rechallenge</a> tests and an analysis of American but not French <a href="/facts/Pharmacovigilance/4v2PDxCM">pharmacovigilance</a> databases indicated a risk of these reactions.<a class="footnote-ref" id="fnref:110" href="#fn:110"><sup>110</sup></a><a class="footnote-ref" id="fnref:111" href="#fn:111"><sup>111</sup></a> </p><p>In clinical trials for <a href="/facts/Osteoarthritis/Iy1wDA1B">osteoarthritis</a>, 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.<a class="footnote-ref" id="fnref:112" href="#fn:112"><sup>112</sup></a> After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating <a href="/facts/Gastrointestinal_bleeding/ynYL5PXm">gastrointestinal bleeding</a> was observed in 20 % of participants, this rate being similar to the ibuprofen group.<a class="footnote-ref" id="fnref:113" href="#fn:113"><sup>113</sup></a> </p><p>Due to the absence of <a href="/facts/Randomized_controlled_trial/LG9lkyVx">controlled studies</a>, most of the information about the long-term safety of paracetamol comes from <a href="/facts/Observational_study/zEhxI4eh">observational studies</a>.<a class="footnote-ref" id="fnref:114" href="#fn:114"><sup>114</sup></a> These indicate a consistent pattern of increased <a href="/facts/Mortality_rate/s4gmxyFV">mortality</a> as well as <a href="/facts/Cardiovascular_disease/HD420nMv">cardiovascular</a> (<a href="/facts/Stroke/DwpjdzY0">stroke</a>, <a href="/facts/Myocardial_infarction/xoGw0qcG">myocardial infarction</a>), gastrointestinal (<a href="/facts/Peptic_ulcer_disease/peMGnYCd">ulcers</a>, <a href="/facts/Gastrointestinal_bleeding/ynYL5PXm">bleeding</a>) and <a href="/facts/Kidney/HBspPrv9">renal</a> adverse effects with increased dose of paracetamol.<a class="footnote-ref" id="fnref:115" href="#fn:115"><sup>115</sup></a><a class="footnote-ref" id="fnref:116" href="#fn:116"><sup>116</sup></a><a class="footnote-ref" id="fnref:117" href="#fn:117"><sup>117</sup></a> Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer.<a class="footnote-ref" id="fnref:118" href="#fn:118"><sup>118</sup></a> 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.<a class="footnote-ref" id="fnref:119" href="#fn:119"><sup>119</sup></a> Meta-analyses suggest that paracetamol may increase the risk of <a href="/facts/Kidney_failure/gsqb5nos">kidney impairment</a> by 23 %<a class="footnote-ref" id="fnref:120" href="#fn:120"><sup>120</sup></a> and kidney cancer by 28 %.<a class="footnote-ref" id="fnref:121" href="#fn:121"><sup>121</sup></a> Paracetamol slightly but significantly increases <a href="/facts/Blood_pressure/VtqqSM2J">blood pressure</a> and heart rate.<a class="footnote-ref" id="fnref:122" href="#fn:122"><sup>122</sup></a> 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.<a class="footnote-ref" id="fnref:123" href="#fn:123"><sup>123</sup></a>[<i>non-primary source needed</i>] 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.<a class="footnote-ref" id="fnref:124" href="#fn:124"><sup>124</sup></a> </p><p>The association between paracetamol use and <a href="/facts/Asthma/7GkJvxn3">asthma</a> in children has been a matter of controversy.<a class="footnote-ref" id="fnref:125" href="#fn:125"><sup>125</sup></a> However, the most recent research suggests that there is no association,<a class="footnote-ref" id="fnref:126" href="#fn:126"><sup>126</sup></a> and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer, ibuprofen.<a class="footnote-ref" id="fnref:127" href="#fn:127"><sup>127</sup></a> </p><p>In recommended doses, the <a href="/facts/Side_effect/PhuX2haY">side effects</a> of paracetamol are mild to non-existent.<a class="footnote-ref" id="fnref:128" href="#fn:128"><sup>128</sup></a> In contrast to aspirin, it is not a <a href="/facts/Antiplatelet_drug/Am8LmCns">blood thinner</a> (and thus may be used in patients where bleeding is a concern), and it does not cause gastric irritation.<a class="footnote-ref" id="fnref:129" href="#fn:129"><sup>129</sup></a> Compared to Ibuprofen—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects.<a class="footnote-ref" id="fnref:130" href="#fn:130"><sup>130</sup></a> Prolonged daily use may cause kidney or liver damage.<a class="footnote-ref" id="fnref:131" href="#fn:131"><sup>131</sup></a><a class="footnote-ref" id="fnref:132" href="#fn:132"><sup>132</sup></a> Paracetamol is metabolized by the liver and is <a href="/facts/Hepatotoxic/xbLcKPNG">hepatotoxic</a>; side effects may be more likely in <a href="/facts/Alcoholism/KGPzpChp">chronic alcoholics</a> or patients with liver damage.<a class="footnote-ref" id="fnref:133" href="#fn:133"><sup>133</sup></a><a class="footnote-ref" id="fnref:134" href="#fn:134"><sup>134</sup></a> </p><p>Until 2010 paracetamol was believed safe in pregnancy however, in a study published in October 2010 it has been linked to <a href="/facts/Infertility/emky9q8L">infertility</a> in the adult life of the unborn.<a class="footnote-ref" id="fnref:135" href="#fn:135"><sup>135</sup></a> 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.<a class="footnote-ref" id="fnref:136" href="#fn:136"><sup>136</sup></a> Unlike aspirin, it is safe for children, as paracetamol is not associated with a risk of <a href="/facts/Reye_syndrome/AP3aX6t3">Reye syndrome</a> in children with viral illnesses.<a class="footnote-ref" id="fnref:137" href="#fn:137"><sup>137</sup></a> Chronic users of paracetamol may have a higher risk of developing <a href="/facts/Hematological_malignancy/tzyyShka">blood cancer</a>.<a class="footnote-ref" id="fnref:138" href="#fn:138"><sup>138</sup></a> </p> <h3>Use in pregnancy</h3> <p>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 <a href="/facts/Birth_defects/ESfzQhTx">birth defects</a>. 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.<a class="footnote-ref" id="fnref:139" href="#fn:139"><sup>139</sup></a> </p><p>Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood <a href="/facts/Asthma/7GkJvxn3">asthma</a>,<a class="footnote-ref" id="fnref:140" href="#fn:140"><sup>140</sup></a><a class="footnote-ref" id="fnref:141" href="#fn:141"><sup>141</sup></a> but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult.<a class="footnote-ref" id="fnref:142" href="#fn:142"><sup>142</sup></a> Paracetamol, in a small-scale meta-analysis was also associated with a 20–30 % increase in <a href="/facts/Autism_spectrum_disorder/bzouRyMI">autism spectrum disorder</a>, <a href="/facts/Attention_deficit_hyperactivity_disorder/uSqjIyhd">attention deficit hyperactivity disorder</a>, and <a href="/facts/Conduct_disorder/yzm78urd">conduct disorder</a>, 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.<a class="footnote-ref" id="fnref:143" href="#fn:143"><sup>143</sup></a><a class="footnote-ref" id="fnref:144" href="#fn:144"><sup>144</sup></a><a class="footnote-ref" id="fnref:145" href="#fn:145"><sup>145</sup></a> 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.<a class="footnote-ref" id="fnref:146" href="#fn:146"><sup>146</sup></a><a class="footnote-ref" id="fnref:147" href="#fn:147"><sup>147</sup></a> In animal experiments, paracetamol disrupts fetal <a href="/facts/Testosterone/uUumdhAz">testosterone</a> production, and several epidemiological studies linked <a href="/facts/Cryptorchidism/QAAoajqa">cryptorchidism</a> 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.<a class="footnote-ref" id="fnref:148" href="#fn:148"><sup>148</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:149" href="#fn:149"><sup>149</sup></a><a class="footnote-ref" id="fnref:150" href="#fn:150"><sup>150</sup></a><a class="footnote-ref" id="fnref:151" href="#fn:151"><sup>151</sup></a> </p><p>In pregnancy, paracetamol and <a href="/facts/Metoclopramide/3Gadd8hg">metoclopramide</a> are deemed safe as are NSAIDs until the <a href="/facts/Third_trimester/vEKYGpep">third trimester</a>.<a class="footnote-ref" id="fnref:152" href="#fn:152"><sup>152</sup></a> </p> <h2 id="overdose">Overdose</h2> <p class="note">Main article: <a href="/facts/Paracetamol_poisoning/eM5q9dj8">Paracetamol poisoning</a></p> <p><a href="/facts/Drug_overdose/Jlo2AX3Y">Overdose</a> of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams),<a class="footnote-ref" id="fnref:153" href="#fn:153"><sup>153</sup></a> and can cause potentially fatal <a href="/facts/Hepatotoxicity/xbLcKPNG">liver damage</a>.<a class="footnote-ref" id="fnref:154" href="#fn:154"><sup>154</sup></a><a class="footnote-ref" id="fnref:155" href="#fn:155"><sup>155</sup></a> 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.<a class="footnote-ref" id="fnref:156" href="#fn:156"><sup>156</sup></a> 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.<a class="footnote-ref" id="fnref:157" href="#fn:157"><sup>157</sup></a> </p><p><a href="/facts/Paracetamol_toxicity/eM5q9dj8">Paracetamol toxicity</a> has become the foremost cause of acute liver failure in the United States by 2003,<a class="footnote-ref" id="fnref:158" href="#fn:158"><sup>158</sup></a> and as of 2005<a href="https://en.wikipedia.org/w/index.php?title=Paracetamol&action=edit">[update]</a>, paracetamol accounted for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.<a class="footnote-ref" id="fnref:159" href="#fn:159"><sup>159</sup></a> As of 2004, paracetamol overdose resulted in more calls to <a href="/facts/Poison_control_center/pVjlgFbv">poison control centers</a> in the U.S. than overdose of any other pharmacological substance.<a class="footnote-ref" id="fnref:160" href="#fn:160"><sup>160</sup></a> 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."<a class="footnote-ref" id="fnref:161" href="#fn:161"><sup>161</sup></a>[<i>needs update</i>] </p><p>Overdoses are frequently related to high-dose <a href="/facts/Recreational_drug_use/eoBD3vKn">recreational use</a> of prescription <a href="/facts/Opioids/EGnE2x99">opioids</a>, as these opioids are most often combined with paracetamol.<a class="footnote-ref" id="fnref:162" href="#fn:162"><sup>162</sup></a> The overdose risk may be heightened by frequent consumption of alcohol.<a class="footnote-ref" id="fnref:163" href="#fn:163"><sup>163</sup></a> </p><p>Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or <a href="/facts/Non-specific_symptom/BzP6MrTN">non-specific symptoms</a>. The first symptoms of overdose usually begin several hours after ingestion, with <a href="/facts/Nausea/dyhkcbeD">nausea</a>, <a href="/facts/Vomiting/R2vQkHqV">vomiting</a>, sweating, and pain as acute liver failure starts.<a class="footnote-ref" id="fnref:164" href="#fn:164"><sup>164</sup></a> 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.<a class="footnote-ref" id="fnref:165" href="#fn:165"><sup>165</sup></a><a class="footnote-ref" id="fnref:166" href="#fn:166"><sup>166</sup></a> </p><p>Treatment is aimed at removing the paracetamol from the body and replenishing <a href="/facts/Glutathione/5bSxjusL">glutathione</a>.<a class="footnote-ref" id="fnref:167" href="#fn:167"><sup>167</sup></a> <a href="/facts/Activated_charcoal/YAbaXCcb">Activated charcoal</a> can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote, <a href="/facts/Acetylcysteine/78TaGKtg">acetylcysteine</a> (also called <i>N</i>-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 <a href="/facts/Liver_transplant/0noMXT50">liver transplant</a> is often required if damage to the liver becomes severe.<a class="footnote-ref" id="fnref:168" href="#fn:168"><sup>168</sup></a><a class="footnote-ref" id="fnref:169" href="#fn:169"><sup>169</sup></a> </p><p>NAC was usually given following a treatment <a href="/facts/Nomogram/ysXLNuVY">nomogram</a> (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.<a class="footnote-ref" id="fnref:170" href="#fn:170"><sup>170</sup></a><a class="footnote-ref" id="fnref:171" href="#fn:171"><sup>171</sup></a> Toxicity of paracetamol is due to its <a href="/facts/1,4-Benzoquinone/Ypl2FyMU">quinone metabolite</a> <a href="/facts/NAPQI/A5KU7k2W">NAPQI</a> and NAC also helps in neutralizing it.<a class="footnote-ref" id="fnref:172" href="#fn:172"><sup>172</sup></a> <a href="/facts/Kidney_failure/gsqb5nos">Kidney failure</a> is also a possible side effect.<a class="footnote-ref" id="fnref:173" href="#fn:173"><sup>173</sup></a> </p> <h2 id="interactions">Interactions</h2> <p><a href="/facts/Prokinetic_agent/1UWsrM0h">Prokinetic agents</a> such as <a href="/facts/Metoclopramide/3Gadd8hg">metoclopramide</a> accelerate gastric emptying, shorten time (tmax) to paracetamol <a href="/facts/Cmax_(pharmacology)/IceQcRQB">peak blood plasma concentration</a> (Cmax), and increase Cmax. Medications slowing gastric emptying such as <a href="/facts/Propantheline/hkT86Ne3">propantheline</a> and <a href="/facts/Morphine/8ngpXHDc">morphine</a> lengthen tmax and decrease Cmax.<a class="footnote-ref" id="fnref:174" href="#fn:174"><sup>174</sup></a><a class="footnote-ref" id="fnref:175" href="#fn:175"><sup>175</sup></a> 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.<a class="footnote-ref" id="fnref:176" href="#fn:176"><sup>176</sup></a> </p><p>There have been suspicions that <a href="/facts/List_of_cytochrome_P450_modulators/7y2gW521">cytochrome inducers</a> may enhance the toxic pathway of paracetamol metabolism to <a href="/facts/NAPQI/A5KU7k2W">NAPQI</a> (see Paracetamol#Pharmacokinetics). By and large, these suspicions have not been confirmed.<a class="footnote-ref" id="fnref:177" href="#fn:177"><sup>177</sup></a> Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for <a href="/facts/Phenobarbital/G236GSuW">phenobarbital</a>, <a href="/facts/Primidone/Pzcme0ww">primidone</a>, <a href="/facts/Isoniazid/kaFX7E6u">isoniazid</a>, and possibly <a href="/facts/St_John%27s_wort/mpjzo2y9">St John's wort</a>.<a class="footnote-ref" id="fnref:178" href="#fn:178"><sup>178</sup></a> On the other hand, the anti-tuberculosis drug <a href="/facts/Isoniazid/kaFX7E6u">isoniazid</a> cuts the formation of NAPQI by 70%.<a class="footnote-ref" id="fnref:179" href="#fn:179"><sup>179</sup></a> </p><p><a href="/facts/Ranitidine/rddBabbF">Ranitidine</a> increased paracetamol <a href="/facts/Area_under_the_curve_(pharmacokinetics)/dyscqaIW">area under the curve</a> (AUC) 1.6-fold. AUC increases are also observed with <a href="/facts/Nizatidine/Lkkecml8">nizatidine</a> and <a href="/facts/Cisapride/9JMdgmW8">cisapride</a>. The effect is explained by these drugs inhibiting <a href="/facts/Glucuronidation/G5qfwsFb">glucuronidation</a> of paracetamol.<a class="footnote-ref" id="fnref:180" href="#fn:180"><sup>180</sup></a> </p><p>Paracetamol raises plasma concentrations of <a href="/facts/Ethinylestradiol/aYRGLz8n">ethinylestradiol</a> by 22 % by inhibiting its sulfation.<a class="footnote-ref" id="fnref:181" href="#fn:181"><sup>181</sup></a> Paracetamol increases <a href="/facts/Prothrombin_time/pkLRGqcY">INR</a> during <a href="/facts/Warfarin/kMnH6tb0">warfarin</a> therapy and should be limited to no more than 2 g per week.<a class="footnote-ref" id="fnref:182" href="#fn:182"><sup>182</sup></a><a class="footnote-ref" id="fnref:183" href="#fn:183"><sup>183</sup></a><a class="footnote-ref" id="fnref:184" href="#fn:184"><sup>184</sup></a> </p> <h2 id="pharmacology">Pharmacology</h2> <h3>Pharmacodynamics</h3> <p>Paracetamol appears to exert its effects through two mechanisms: the inhibition of <a href="/facts/Cyclooxygenase/L2HFqExc">cyclooxygenase</a> (COX) and actions of its metabolite <a href="/facts/N-arachidonoylphenolamine/MpBygfQU"><i>N</i>-arachidonoylphenolamine</a> (AM404).<a class="footnote-ref" id="fnref:185" href="#fn:185"><sup>185</sup></a> </p><p>Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting <a href="/facts/COX-1/obt43Mow">COX-1</a> and <a href="/facts/COX-2/VMWBjyN8">COX-2</a> enzymes and especially similar to selective <a href="/facts/COX-2_inhibitor/UpxLSTyN">COX-2 inhibitors</a>.<a class="footnote-ref" id="fnref:186" href="#fn:186"><sup>186</sup></a> Paracetamol inhibits <a href="/facts/Prostaglandin/kIKw0gDj">prostaglandin</a> synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of <a href="/facts/Arachidonic_acid/7fMTra6z">arachidonic acid</a> and <a href="/facts/Organic_peroxide/UAyyVaDU">peroxides</a> 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.<a class="footnote-ref" id="fnref:187" href="#fn:187"><sup>187</sup></a><a class="footnote-ref" id="fnref:188" href="#fn:188"><sup>188</sup></a> The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the <a href="/facts/Central_nervous_system/k8I6To97">central nervous system</a> and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding. </p><p>The second mechanism centers on the paracetamol metabolite <a href="/facts/AM404/MpBygfQU">AM404</a>. This metabolite has been detected in the brains of animals and <a href="/facts/Cerebrospinal_fluid/tcWG7hhv">cerebrospinal fluid</a> of humans taking paracetamol.<a class="footnote-ref" id="fnref:189" href="#fn:189"><sup>189</sup></a><a class="footnote-ref" id="fnref:190" href="#fn:190"><sup>190</sup></a> It is formed in the brain from another paracetamol metabolite <a href="/facts/4-aminophenol/B2u4nyWM">4-aminophenol</a> by action of <a href="/facts/Fatty_acid_amide_hydrolase/R11qaeBq">fatty acid amide hydrolase</a>.<a class="footnote-ref" id="fnref:191" href="#fn:191"><sup>191</sup></a> AM404 is a weak agonist of cannabinoid receptors <a href="/facts/Cannabinoid_receptor_type_1/7b2tfePV">CB1</a> and <a href="/facts/Cannabinoid_receptor_type_2/JEXD2WjV">CB2</a>, an inhibitor of <a href="/facts/Endocannabinoid_transporter/g13SlQb1">endocannabinoid transporter</a>, and a potent activator of <a href="/facts/TRPV1/ju5REhRu">TRPV1</a> receptor.<a class="footnote-ref" id="fnref:192" href="#fn:192"><sup>192</sup></a> This and other research indicate that the <a href="/facts/Endocannabinoid_system/eIpB5GFm">endocannabinoid system</a> and TRPV1 may play an important role in the analgesic effect of paracetamol.<a class="footnote-ref" id="fnref:193" href="#fn:193"><sup>193</sup></a><a class="footnote-ref" id="fnref:194" href="#fn:194"><sup>194</sup></a> </p><p>In 2018, Suemaru <i>et al</i>. found that, in mice, paracetamol exerts an anticonvulsant effect by activation of the <a href="/facts/TRPV1/ju5REhRu">TRPV1</a> receptors<a class="footnote-ref" id="fnref:195" href="#fn:195"><sup>195</sup></a> and a decrease in neuronal excitability by <a href="/facts/Hyperpolarization_(biology)/XNH4zPwN">hyperpolarization</a> of neurons.<a class="footnote-ref" id="fnref:196" href="#fn:196"><sup>196</sup></a> The exact mechanism of the anticonvulsant effect of paracetamol is not clear. According to Suemaru <i>et al</i>., acetaminophen and its active metabolite <a href="/facts/AM404/MpBygfQU">AM404</a> show a dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice.<a class="footnote-ref" id="fnref:197" href="#fn:197"><sup>197</sup></a> </p> <h3>Pharmacokinetics</h3> <p>After being taken by mouth, paracetamol is rapidly absorbed from the <a href="/facts/Small_intestine/1AQ8RJ4m">small intestine</a>, 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.<a class="footnote-ref" id="fnref:198" href="#fn:198"><sup>198</sup></a> 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.<a class="footnote-ref" id="fnref:199" href="#fn:199"><sup>199</sup></a> </p><p>Paracetamol's <a href="/facts/Bioavailability/9l6na9MV">bioavailability</a> is dose-dependent: it increases from 63 % for 500 mg dose to 89 % for 1000 mg dose.<a class="footnote-ref" id="fnref:200" href="#fn:200"><sup>200</sup></a> Its plasma terminal elimination half-life is 1.9–2.5 hours,<a class="footnote-ref" id="fnref:201" href="#fn:201"><sup>201</sup></a> and <a href="/facts/Volume_of_distribution/64B8XegG">volume of distribution</a> is roughly 50 L.<a class="footnote-ref" id="fnref:202" href="#fn:202"><sup>202</sup></a> Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21 %.<a class="footnote-ref" id="fnref:203" href="#fn:203"><sup>203</sup></a> The concentration in serum after a typical dose of paracetamol usually peaks below 30 μg/mL (200 μmol/L).<a class="footnote-ref" id="fnref:204" href="#fn:204"><sup>204</sup></a> After 4 hours, the concentration is usually less than 10 μg/mL (66 μmol/L).<a class="footnote-ref" id="fnref:205" href="#fn:205"><sup>205</sup></a> </p> <p>Paracetamol is <a href="/facts/Drug_metabolism/I5nQ28Ma">metabolized</a> primarily in the liver, mainly by <a href="/facts/Glucuronidation/G5qfwsFb">glucuronidation</a> and <a href="/facts/Sulfation/lI6B3Y1M">sulfation</a>, 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.<a class="footnote-ref" id="fnref:206" href="#fn:206"><sup>206</sup></a> Glucuronidation by <a href="/facts/UGT1A1/I0KqSo8Q">UGT1A1</a> and <a href="/facts/UGT1A6/SNxWUE73">UGT1A6</a> accounts for 50–70 % of the drug metabolism. Additional 25–35 % of paracetamol is converted to sulfate by sulfation enzymes <a href="/facts/SULT1A1/aCQ1KLcc">SULT1A1</a>, <a href="/facts/SULT1A3/B4TfltUG">SULT1A3</a>, and <a href="/facts/SULT1E1/4E96usyJ">SULT1E1</a>.<a class="footnote-ref" id="fnref:207" href="#fn:207"><sup>207</sup></a> </p><p>A minor metabolic pathway (5–15 %) of oxidation by <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> enzymes, mainly by <a href="/facts/CYP2E1/T8RrnGdW">CYP2E1</a>, forms a toxic metabolite known as <a href="/facts/NAPQI/A5KU7k2W">NAPQI</a> (<i>N</i>-acetyl-<i>p</i>-benzoquinone imine).<a class="footnote-ref" id="fnref:208" href="#fn:208"><sup>208</sup></a> NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with <a href="/facts/Glutathione/5bSxjusL">glutathione</a>. 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 <a href="/facts/Mitochondria/ErHqrdJ1">mitochondria</a> proteins of the liver cells causing <a href="/facts/Oxidative_stress/HX7dfUUb">oxidative stress</a> and toxicity.<a class="footnote-ref" id="fnref:209" href="#fn:209"><sup>209</sup></a> </p><p>Yet another minor but important direction of metabolism is deacetylation of 1–2 % of paracetamol to form <a href="/facts/P-Aminophenol/B2u4nyWM"><i>p</i>-aminophenol</a>. <i>p</i>-Aminophenol is then converted in the brain by <a href="/facts/Fatty_acid_amide_hydrolase/R11qaeBq">fatty acid amide hydrolase</a> into <a href="/facts/AM404/MpBygfQU">AM404</a>, a compound that may be partially responsible for the analgesic action of paracetamol.<a class="footnote-ref" id="fnref:210" href="#fn:210"><sup>210</sup></a> </p> <h2 id="chemistry">Chemistry</h2> <h3>Synthesis</h3> <h4>Classical methods</h4> <p>The classical methods for the production of paracetamol involve the <a href="/facts/Acetylation/PNMzRM4r">acetylation</a> of <a href="/facts/4-aminophenol/B2u4nyWM">4-aminophenol</a> with <a href="/facts/Acetic_anhydride/hGxHam3M">acetic anhydride</a> as the last step. They differ in how 4-aminophenol is prepared. In one method, <a href="/facts/Nitration/VnszL09H">nitration</a> of <a href="/facts/Phenol/ACJs5NIU">phenol</a> with <a href="/facts/Nitric_acid/UDbwGp6s">nitric acid</a> affords <a href="/facts/4-nitrophenol/u2AXK9aN">4-nitrophenol</a>, which is reduced to 4-aminophenol by <a href="/facts/Hydrogenation/l7EzNSA7">hydrogenation</a> over <a href="/facts/Raney_nickel/y4CnrEXv">Raney nickel</a>. In another method, <a href="/facts/Nitrobenzene/JCEYpjAA">nitrobenzene</a> is reduced <a href="/facts/Electrolysis/pU75nCDI">electrolytically</a> giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by <a href="/facts/Tin(II)_chloride/4TdjMLEk">Tin(II) Chloride</a> in <a href="/facts/Absolute_ethanol/3lCLfBSP">absolute ethanol</a> or <a href="/facts/Ethyl_acetate/om0PFI7S">ethyl acetate</a> to produce a 91 % yield of 4-aminophenol.<a class="footnote-ref" id="fnref:211" href="#fn:211"><sup>211</sup></a><a class="footnote-ref" id="fnref:212" href="#fn:212"><sup>212</sup></a><a class="footnote-ref" id="fnref:213" href="#fn:213"><sup>213</sup></a> </p> <h4>Celanese synthesis</h4> <p>An alternative industrial synthesis developed at <a href="/facts/Celanese/kwD26m5Y">Celanese</a> involves firstly direct acylation of phenol with acetic anhydride in the presence of <a href="/facts/Hydrogen_fluoride/XfQxlqR6">hydrogen fluoride</a> to a ketone, then the conversion of the ketone with <a href="/facts/Hydroxylamine/BXzuazgo">hydroxylamine</a> to a <a href="/facts/Ketoxime/xRlPfB6K">ketoxime</a>, and finally the acid-catalyzed <a href="/facts/Beckmann_rearrangement/fYoqh7H3">Beckmann rearrangement</a> of the cetoxime to the para-acetylaminophenol product.<a class="footnote-ref" id="fnref:214" href="#fn:214"><sup>214</sup></a><a class="footnote-ref" id="fnref:215" href="#fn:215"><sup>215</sup></a> </p> <h3>Reactions</h3> <p><i>4</i>-Aminophenol may be obtained by the amide <a href="/facts/Hydrolysis/JTvwIHPs">hydrolysis</a> of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, <i>4</i>-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an <a href="/facts/Indophenol/vMhYnT7a">indophenol</a> dye under oxidization by air.<a class="footnote-ref" id="fnref:216" href="#fn:216"><sup>216</sup></a> </p> <h2 id="history">History</h2> <p><a href="/facts/Acetanilide/sEcTq9pz">Acetanilide</a> was the first <a href="/facts/Aniline/eFXck1Rj">aniline</a> derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of <a href="/facts/Antifebrin/sEcTq9pz">Antifebrin</a> by Cahn & Hepp in 1886.<a class="footnote-ref" id="fnref:217" href="#fn:217"><sup>217</sup></a> But its unacceptable toxic effects—the most alarming being <a href="/facts/Cyanosis/V7ynzIjn">cyanosis</a> due to <a href="/facts/Methemoglobinemia/UK2NhkuM">methemoglobinemia</a>, an increase of hemoglobin in its ferric [Fe3+] state, called <a href="/facts/Methemoglobin/eTPQFl0A">methemoglobin</a>, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue—prompted the search for less toxic aniline derivatives.<a class="footnote-ref" id="fnref:218" href="#fn:218"><sup>218</sup></a> Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.<a class="footnote-ref" id="fnref:219" href="#fn:219"><sup>219</sup></a><a class="footnote-ref" id="fnref:220" href="#fn:220"><sup>220</sup></a> </p><p><a href="/facts/Harmon_Northrop_Morse/1G7bNYUu">Harmon Northrop Morse</a> synthesized paracetamol at <a href="/facts/Johns_Hopkins_University/56US0mHw">Johns Hopkins University</a> via the reduction of <a href="/facts/4-Nitrophenol/u2AXK9aN"><i>p</i>-nitrophenol</a> with <a href="/facts/Tin/obW9mqc3">tin</a> in glacial <a href="/facts/Acetic_acid/uyBKA2Pd">acetic acid</a> in 1877,<a class="footnote-ref" id="fnref:221" href="#fn:221"><sup>221</sup></a><a class="footnote-ref" id="fnref:222" href="#fn:222"><sup>222</sup></a> but it was not until 1887 that clinical pharmacologist <a href="/facts/Joseph_von_Mering/v9MLySkE">Joseph von Mering</a> tried paracetamol on humans.<a class="footnote-ref" id="fnref:223" href="#fn:223"><sup>223</sup></a> In 1893, von Mering published a paper reporting on the clinical results of paracetamol with <a href="/facts/Phenacetin/Ij00CRxt">phenacetin</a>, another aniline derivative.<a class="footnote-ref" id="fnref:224" href="#fn:224"><sup>224</sup></a> Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce <a href="/facts/Methemoglobinemia/UK2NhkuM">methemoglobinemia</a>. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established <a href="/facts/Bayer/fnYepBcG">Bayer</a> as a leading pharmaceutical company.<a class="footnote-ref" id="fnref:225" href="#fn:225"><sup>225</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:226" href="#fn:226"><sup>226</sup></a> In 1947, <a href="/facts/David_Lester_(biochemist)/1bxYKQIG">David Lester</a> 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.<a class="footnote-ref" id="fnref:227" href="#fn:227"><sup>227</sup></a> In 1948, <a href="/facts/Bernard_Brodie_(biochemist)/rm47n5vb">Bernard Brodie</a>, <a href="/facts/Julius_Axelrod/RfxCLUgC">Julius Axelrod</a> 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.<a class="footnote-ref" id="fnref:228" href="#fn:228"><sup>228</sup></a><a class="footnote-ref" id="fnref:229" href="#fn:229"><sup>229</sup></a><a class="footnote-ref" id="fnref:230" href="#fn:230"><sup>230</sup></a> They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, <a href="/facts/Phenylhydroxylamine/4bH18Pva">phenylhydroxylamine</a>. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.<a class="footnote-ref" id="fnref:231" href="#fn:231"><sup>231</sup></a> This led to a "rediscovery" of paracetamol.<a class="footnote-ref" id="fnref:232" href="#fn:232"><sup>232</sup></a> </p><p>Paracetamol was first marketed in the United States in 1950 under the name Trigesic, a combination of paracetamol, aspirin, and caffeine.<a class="footnote-ref" id="fnref:233" href="#fn:233"><sup>233</sup></a> Reports in 1951 of three users stricken with the blood disease <a href="/facts/Agranulocytosis/3AP5MDpD">agranulocytosis</a> led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected.<a class="footnote-ref" id="fnref:234" href="#fn:234"><sup>234</sup></a> The following year, 1952, paracetamol returned to the U.S. market as a prescription drug.<a class="footnote-ref" id="fnref:235" href="#fn:235"><sup>235</sup></a> In the United Kingdom, marketing of paracetamol began in 1956 by <a href="/facts/Sterling-Winthrop_Co./Xq8YbRPj">Sterling-Winthrop Co.</a> as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers.<a class="footnote-ref" id="fnref:236" href="#fn:236"><sup>236</sup></a><a class="footnote-ref" id="fnref:237" href="#fn:237"><sup>237</sup></a> In 1963, paracetamol was added to the <i><a href="/facts/British_Pharmacopoeia/1qE4pIfM">British Pharmacopoeia</a></i>, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.<a class="footnote-ref" id="fnref:238" href="#fn:238"><sup>238</sup></a><a class="footnote-ref" id="fnref:239" href="#fn:239"><sup>239</sup></a> </p><p>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 <a href="/facts/Analgesic_nephropathy/0CyKMdG7">analgesic nephropathy</a> and hematological toxicity.<a class="footnote-ref" id="fnref:240" href="#fn:240"><sup>240</sup></a> Available in the U.S. without a prescription since 1955<a class="footnote-ref" id="fnref:241" href="#fn:241"><sup>241</sup></a> (1960, according to another source<a class="footnote-ref" id="fnref:242" href="#fn:242"><sup>242</sup></a>), paracetamol has become a common household drug.<a class="footnote-ref" id="fnref:243" href="#fn:243"><sup>243</sup></a> In 1988, Sterling Winthrop was acquired by <a href="/facts/Eastman_Kodak/zMnK74Cp">Eastman Kodak</a> which sold the over the counter drug rights to <a href="/facts/SmithKline_Beecham/NrnnxFNW">SmithKline Beecham</a> in 1994.<a class="footnote-ref" id="fnref:244" href="#fn:244"><sup>244</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:245" href="#fn:245"><sup>245</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:246" href="#fn:246"><sup>246</sup></a><a class="footnote-ref" id="fnref:247" href="#fn:247"><sup>247</sup></a><a class="footnote-ref" id="fnref:248" href="#fn:248"><sup>248</sup></a><a class="footnote-ref" id="fnref:249" href="#fn:249"><sup>249</sup></a><a class="footnote-ref" id="fnref:250" href="#fn:250"><sup>250</sup></a> Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.<a class="footnote-ref" id="fnref:251" href="#fn:251"><sup>251</sup></a><a class="footnote-ref" id="fnref:252" href="#fn:252"><sup>252</sup></a> </p><p>In November 2011, the <a href="/facts/Medicines_and_Healthcare_products_Regulatory_Agency/6T727R0c">Medicines and Healthcare products Regulatory Agency</a> revised UK dosing of liquid paracetamol for children.<a class="footnote-ref" id="fnref:253" href="#fn:253"><sup>253</sup></a> </p><p>In September 2013, "Use Only as Directed", an episode of the radio program <i><a href="/facts/This_American_Life/Kr0RwmFg">This American Life</a></i><a class="footnote-ref" id="fnref:254" href="#fn:254"><sup>254</sup></a> highlighted deaths from paracetamol overdose. This report was followed by two reports by <a href="/facts/ProPublica/BKrCjSrD">ProPublica</a> 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"<a class="footnote-ref" id="fnref:255" href="#fn:255"><sup>255</sup></a> and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."<a class="footnote-ref" id="fnref:256" href="#fn:256"><sup>256</sup></a> </p> <h2 id="society-and-culture">Society and culture</h2> <h3>Naming</h3> <p><i>Paracetamol</i> is the <a href="/facts/Australian_Approved_Name/lLXrcJ5F">Australian Approved Name</a><a class="footnote-ref" id="fnref:257" href="#fn:257"><sup>257</sup></a> and <a href="/facts/British_Approved_Name/pm1t52SQ">British Approved Name</a><a class="footnote-ref" id="fnref:258" href="#fn:258"><sup>258</sup></a> as well as the <a href="/facts/International_nonproprietary_name/wYL655x6">international nonproprietary name</a> used by the WHO and in many other countries; <i>acetaminophen</i> is the <a href="/facts/United_States_Adopted_Name/5AFEKGfQ">United States Adopted Name</a><a class="footnote-ref" id="fnref:259" href="#fn:259"><sup>259</sup></a> and <a href="/facts/Japanese_Accepted_Name/2TWpxztK">Japanese Accepted Name</a> and also the name generally used in Canada,<a class="footnote-ref" id="fnref:260" href="#fn:260"><sup>260</sup></a> Venezuela, Colombia, and Iran.<a class="footnote-ref" id="fnref:261" href="#fn:261"><sup>261</sup></a><a class="footnote-ref" id="fnref:262" href="#fn:262"><sup>262</sup></a> Both <i>paracetamol</i> and <i>acetaminophen</i> are contractions of chemical names for the compound. The word "paracetamol" is a shortened form of para-acetylaminophenol,<a class="footnote-ref" id="fnref:263" href="#fn:263"><sup>263</sup></a> and was coined by Frederick Stearns & Co in 1956,<a class="footnote-ref" id="fnref:264" href="#fn:264"><sup>264</sup></a> 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.<a class="footnote-ref" id="fnref:265" href="#fn:265"><sup>265</sup></a> The initialism <i>APAP</i> is used by dispensing pharmacists in the United States.<a class="footnote-ref" id="fnref:266" href="#fn:266"><sup>266</sup></a> </p> <h3>Available forms</h3> <p class="note">See also: <a href="/facts/Paracetamol_brand_names/houSG9WQ">Paracetamol brand names</a></p> <p>Paracetamol is available in oral, suppository, and <a href="/facts/Intravenous/AwwuD3Nu">intravenous</a> forms.<a class="footnote-ref" id="fnref:267" href="#fn:267"><sup>267</sup></a> Intravenous paracetamol is sold under the brand name Ofirmev in the United States.<a class="footnote-ref" id="fnref:268" href="#fn:268"><sup>268</sup></a> </p><p>In some formulations, paracetamol is combined with the <a href="/facts/Opiate/IHfQkMkU">opiate</a> <a href="/facts/Codeine/lr7WHXmX">codeine</a>, sometimes referred to as <a href="/facts/Co-codamol/WhMVYNNG">co-codamol</a> (<a href="/facts/British_Approved_Name/pm1t52SQ">BAN</a>) and Panadeine in Australia. In the U.S., this combination is available only by prescription.<a class="footnote-ref" id="fnref:269" href="#fn:269"><sup>269</sup></a> As of 1 February 2018, medications containing codeine also became prescription-only in Australia.<a class="footnote-ref" id="fnref:270" href="#fn:270"><sup>270</sup></a> Paracetamol is also combined with other opioids such as <a href="/facts/Dihydrocodeine/tq4PUfdb">dihydrocodeine</a>,<a class="footnote-ref" id="fnref:271" href="#fn:271"><sup>271</sup></a> referred to as <a href="/facts/Co-dydramol/l6faBM0r">co-dydramol</a> (<a href="/facts/British_Approved_Name/pm1t52SQ">British Approved Name</a> (BAN)), <a href="/facts/Oxycodone/mv95L2c7">oxycodone</a><a class="footnote-ref" id="fnref:272" href="#fn:272"><sup>272</sup></a> or <a href="/facts/Hydrocodone/PjvCI4wN">hydrocodone</a>.<a class="footnote-ref" id="fnref:273" href="#fn:273"><sup>273</sup></a> Another very commonly used analgesic combination includes paracetamol in combination with <a href="/facts/Propoxyphene_napsylate/wjh8HcC2">propoxyphene napsylate</a>.<a class="footnote-ref" id="fnref:274" href="#fn:274"><sup>274</sup></a> A combination of paracetamol, codeine, and the <a href="/facts/Doxylamine/sCBJP1sc">doxylamine succinate</a> is also available.<a class="footnote-ref" id="fnref:275" href="#fn:275"><sup>275</sup></a> </p><p>Paracetamol is sometimes combined with <a href="/facts/Phenylephrine_hydrochloride/sf4DxQws">phenylephrine hydrochloride</a>.<a class="footnote-ref" id="fnref:276" href="#fn:276"><sup>276</sup></a> Sometimes a third active ingredient, such as <a href="/facts/Ascorbic_acid/IA2f1fTm">ascorbic acid</a>,<a class="footnote-ref" id="fnref:277" href="#fn:277"><sup>277</sup></a><a class="footnote-ref" id="fnref:278" href="#fn:278"><sup>278</sup></a> <a href="/facts/Caffeine/Hx6E2QC5">caffeine</a>,<a class="footnote-ref" id="fnref:279" href="#fn:279"><sup>279</sup></a><a class="footnote-ref" id="fnref:280" href="#fn:280"><sup>280</sup></a> <a href="/facts/Chlorphenamine/fuBFmrko">chlorpheniramine maleate</a>,<a class="footnote-ref" id="fnref:281" href="#fn:281"><sup>281</sup></a> or <a href="/facts/Guaifenesin/6M5ShWzC">guaifenesin</a><a class="footnote-ref" id="fnref:282" href="#fn:282"><sup>282</sup></a><a class="footnote-ref" id="fnref:283" href="#fn:283"><sup>283</sup></a><a class="footnote-ref" id="fnref:284" href="#fn:284"><sup>284</sup></a> is added to this combination. </p> <h2 id="research">Research</h2> <p>Claims that paracetamol is an effective analgesic medication to treat symptoms of <a href="/facts/COVID-19/YsUgvsaX">COVID-19</a> were found to be unsubstantiated.<a class="footnote-ref" id="fnref:285" href="#fn:285"><sup>285</sup></a><a class="footnote-ref" id="fnref:286" href="#fn:286"><sup>286</sup></a><a class="footnote-ref" id="fnref:287" href="#fn:287"><sup>287</sup></a><a class="footnote-ref" id="fnref:288" href="#fn:288"><sup>288</sup></a> </p> <h2 id="veterinary-use">Veterinary use</h2> <h3>Cats</h3> <p>Paracetamol is extremely toxic to cats, which lack the necessary <a href="/facts/UGT1A6/SNxWUE73">UGT1A6</a> 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, <a href="/facts/Methemoglobin/eTPQFl0A">methemoglobin</a> formation and the production of <a href="/facts/Heinz_bodies/uhKKKN4p">Heinz bodies</a> in red blood cells inhibit oxygen transport by the blood, causing <a href="/facts/Asphyxiation/bahl3DJf">asphyxiation</a> (<a href="/facts/Methemoglobinemia/UK2NhkuM">methemoglobinemia</a> and <a href="/facts/Hemolytic_anemia/qNz6wDct">hemolytic anemia</a>).<a class="footnote-ref" id="fnref:289" href="#fn:289"><sup>289</sup></a> Treatment of the toxicosis with <a href="/facts/Acetylcysteine/78TaGKtg">acetylcysteine</a> is recommended.<a class="footnote-ref" id="fnref:290" href="#fn:290"><sup>290</sup></a> </p> <h3>Dogs</h3> <p>Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.<a class="footnote-ref" id="fnref:291" href="#fn:291"><sup>291</sup></a> A paracetamol–codeine product (brand name Pardale-V)<a class="footnote-ref" id="fnref:292" href="#fn:292"><sup>292</sup></a> licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person.<a class="footnote-ref" id="fnref:293" href="#fn:293"><sup>293</sup></a> It should be administered to dogs only on veterinary advice and with extreme caution.<a class="footnote-ref" id="fnref:294" href="#fn:294"><sup>294</sup></a> </p><p>The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.<a class="footnote-ref" id="fnref:295" href="#fn:295"><sup>295</sup></a><a class="footnote-ref" id="fnref:296" href="#fn:296"><sup>296</sup></a><a class="footnote-ref" id="fnref:297" href="#fn:297"><sup>297</sup></a><a class="footnote-ref" id="fnref:298" href="#fn:298"><sup>298</sup></a> Acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.<a class="footnote-ref" id="fnref:299" href="#fn:299"><sup>299</sup></a><a class="footnote-ref" id="fnref:300" href="#fn:300"><sup>300</sup></a> </p> <h3>Snakes</h3> <p>Paracetamol is lethal to snakes<a class="footnote-ref" id="fnref:301" href="#fn:301"><sup>301</sup></a> and has been suggested as a chemical control program for the invasive <a href="/facts/Brown_tree_snake/Pgfss9d1">brown tree snake</a> (<i>Boiga irregularis</i>) in <a href="/facts/Guam/z77Ql3fM">Guam</a>.<a class="footnote-ref" id="fnref:302" href="#fn:302"><sup>302</sup></a><a class="footnote-ref" id="fnref:303" href="#fn:303"><sup>303</sup></a> Doses of 80 mg are inserted into dead mice that are scattered by helicopter<a class="footnote-ref" id="fnref:304" href="#fn:304"><sup>304</sup></a> as lethal bait to be consumed by the snakes. </p> <h2 id="notes">Notes</h2> <h2 id="external-links">External links</h2> Wikimedia Commons has media related to Paracetamol. <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Used by the World Health Organization (WHO) <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Commonly called "acetaminophen" in the United States, Canada, Japan, South Korea, Colombia and Venezuela <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Prescott LF (March 2000). "Paracetamol: past, present, and future". American Journal of Therapeutics. 7 (2): 143–147. doi:10.1097/00045391-200007020-00011. PMID 11319582. S2CID 7754908. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Warwick C (November 2008). "Paracetamol and fever management". J R Soc Promot Health. 128 (6): 320–323. doi:10.1177/1466424008092794. PMID 19058473. S2CID 25702228. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Saragiotto BT, Abdel Shaheed C, Maher CG (December 2019). "Paracetamol for pain in adults". BMJ. 367: l6693. doi:10.1136/bmj.l6693. PMID 31892511. 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