|Classification and external resources|
Paracetamol toxicity is caused by excessive use or overdose of the analgesic drug paracetamol (called acetaminophen in North America). Mainly causing liver injury, paracetamol toxicity is one of the most common causes of poisoning worldwide. In the United States and the United Kingdom it is the most common cause of acute liver failure.
Many individuals with paracetamol toxicity may have no symptoms at all in the first 24 hours following overdose. Others may initially have nonspecific complaints such as vague abdominal pain and nausea. With progressive disease, signs of liver failure may develop; these include low blood sugar, low blood pH, easy bleeding, and hepatic encephalopathy. Some will spontaneously resolve, although untreated cases may result in death.
Damage to the liver, or hepatotoxicity, results not from paracetamol itself, but from one of its metabolites, N-acetyl-p-benzoquinoneimine (NAPQI)(also known as N-acetylimidoquinone). NAPQI depletes the liver's natural antioxidant glutathione and directly damages cells in the liver, leading to liver failure. Risk factors for toxicity include excessive chronic alcohol intake, fasting or anorexia nervosa, and the use of certain drugs such as isoniazid.
Treatment is aimed at removing the paracetamol from the body and replacing glutathione. Activated charcoal can be used to decrease absorption of paracetamol if the patient presents for treatment soon after the overdose; the antidote acetylcysteine acts as a precursor for glutathione, helping the body regenerate enough to prevent damage to the liver. N-acetylcysteine can neutralize NAPQI by itself as well. A liver transplant is often required if damage to the liver becomes severe. Patients treated early have a good prognosis, whereas patients that develop major liver abnormalities typically have a poor outcome. Efforts to prevent paracetamol overdose include limiting individual sales of the drug and combining paracetamol with methionine, which is converted into glutathione in the liver.
- 1 Toxicity
- 2 Signs and symptoms
- 3 Pathophysiology
- 4 Diagnosis
- 5 Detection in body fluids
- 6 Prevention
- 7 Treatment
- 8 Prognosis
- 9 Epidemiology
- 10 References
- 11 Further reading
The toxic dose of paracetamol is highly variable. In general the recommended maximum daily dose for healthy adults is 4 grams. Higher doses lead to increasing risk of toxicity. In adults, single doses above 10 grams or 200 mg/kg of bodyweight, whichever is lower, have a reasonable likelihood of causing toxicity. Toxicity can also occur when multiple smaller doses within 24 hours exceeds these levels. Following a normal dose of 1 gram of paracetamol four times a day for two weeks, patients can expect an increase in alanine transaminase in their liver to typically about three times the normal value. It is unlikely that this dose would lead to liver failure. Studies have shown significant hepatotoxicity is uncommon in patients who have taken greater than normal doses over 3 to 4 days. In adults, a dose of 6 grams a day over the preceding 48 hours could potentially lead to toxicity, while in children acute doses above 200 mg/kg could potentially cause toxicity. Acute paracetamol overdose in children rarely causes illness or death, and it is very uncommon for children to have levels that require treatment, with chronic larger-than-normal doses being the major cause of toxicity in children. Intravenous doses should be smaller than those taken orally, all other things being equal.
In rare individuals, paracetamol toxicity can result from normal use. This may be due to individual ("idiosyncratic") differences in the expression and activity of certain enzymes in one of the metabolic pathways that handle paracetamol (see paracetamol's metabolism).
Signs and symptoms
The signs and symptoms of paracetamol toxicity occur in three phases. The first phase begins within hours of overdose, and consists of nausea, vomiting, pallor, and sweating. However, patients often have no specific symptoms or only mild symptoms in the first 24 hours of poisoning. Rarely, after massive overdoses, patients may develop symptoms of metabolic acidosis and coma early in the course of poisoning.
The second phase occurs between 24 and 72 hours following overdose and consists of signs of increasing liver damage. In general, damage occurs in hepatocytes as they metabolize the paracetamol. The individual may experience right-upper-quadrant pain. The increasing liver damage also alters biochemical markers of liver function; International normalized ratio (INR) and the hepatic transaminases alanine transaminase and aspartate transaminase rise to abnormal levels. Acute kidney failure may also occur during this phase, typically caused by either hepatorenal syndrome or multiple organ dysfunction syndrome. In some cases, acute kidney failure may be the primary clinical manifestation of toxicity. In these cases, it has been suggested that the toxic metabolite is produced more in the kidneys than in the liver.
The third phase follows at 3 to 5 days, and is marked by complications of massive hepatic necrosis leading to fulminant hepatic failure with complications of coagulation defects, hypoglycemia, kidney failure, hepatic encephalopathy, cerebral edema, sepsis, multiple organ failure, and death. If the third phase is survived, the hepatic necrosis runs its course, and liver and kidney function typically return to normal in a few weeks. The severity of paracetamol toxicity varies depending on the dose and whether appropriate treatment is received.
When taken in normal therapeutic doses, paracetamol has been shown to be safe. Following a therapeutic dose, it is mostly converted to nontoxic metabolites via Phase II metabolism by conjugation with sulfate and glucuronide, with a small portion being oxidized via the cytochrome P450 enzyme system. Cytochromes P450 2E1 and 3A4 convert approximately 5% of paracetamol to a highly-reactive intermediary metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). Under normal conditions, NAPQI is detoxified by conjugation with glutathione to form cysteine and mercapturic acid conjugates.
In cases of paracetamol overdose, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. As a result, hepatocellular supplies of glutathione become depleted, as the demand for glutathione is higher than its regeneration. NAPQI therefore remains in its toxic form in the liver and reacts with cellular membrane molecules, resulting in widespread hepatocyte damage and death, leading to acute hepatic necrosis. In animal studies, hepatic glutathione must be depleted to less than 70% of normal levels before hepatotoxicity occurs.
A number of factors can potentially increase the risk of developing paracetamol toxicity. Chronic excessive alcohol consumption can induce CYP2E1, thus increasing the potential toxicity of paracetamol. Whether chronic alcoholism should be considered a risk factor has been debated by some clinical toxicologists. For chronic alcohol users, acute alcohol ingestion at the time of a paracetamol overdose may have a protective effect. For non-chronic alcohol users, acute alcohol consumption had no protective effect.
Fasting is a risk factor, possibly because of depletion of hepatic glutathione reserves. The concomitant use of the CYP2E1 inhibitor isoniazid increases the risk of hepatotoxicity, though whether 2E1 induction is related to the hepatotoxicity in this case is unclear. Concomitant use of other drugs that induce CYP enzymes, such as antiepileptics including carbamazepine, phenytoin, and barbiturates, have also been reported as risk factors.
The most effective way to diagnose poisoning is by obtaining a blood paracetamol level. A drug nomogram developed in 1975, called the Rumack-Matthew nomogram, estimates the risk of toxicity based on the serum concentration of paracetamol at a given number of hours after ingestion. To determine the risk of potential hepatotoxicity, the paracetamol level is traced along the nomogram. Use of a timed serum paracetamol level plotted on the nomogram appears to be the best marker indicating the potential for liver injury. A paracetamol level drawn in the first four hours after ingestion may underestimate the amount in the system because paracetamol may still be in the process of being absorbed from the gastrointestinal tract. Therefore a serum level taken before 4 hours is not recommended.
Clinical or biochemical evidence of liver toxicity may develop in one to four days, although, in severe cases, it may be evident in 12 hours. Right-upper-quadrant tenderness may be present and can aid in diagnosis. Laboratory studies may show evidence of hepatic necrosis with elevated AST, ALT, bilirubin, and prolonged coagulation times, particularly an elevated prothrombin time. After paracetamol overdose, when AST and ALT exceed 1000 IU/L, paracetamol-induced hepatotoxicity can be diagnosed. In some cases, the AST and ALT levels can exceed 10,000 IU/L.
Detection in body fluids
Paracetamol may be quantified in blood, plasma, or urine as a diagnostic tool in clinical poisoning situations or to aid in the medicolegal investigation of suspicious deaths. Plasma concentrations during therapy usually range from 2-20 mg/L, whereas levels of 30-300 mg/L are often observed in overdose patients. Postmortem blood levels have ranged from 50-400 mg/L in persons dying due to acute overdosage. Automated colorimetric techniques, gas chromatography and liquid chromatography are currently in use for the laboratory analysis of the drug in physiological specimens.
Combination with Other Agents
There have been no studies so far on the effectiveness of paracetamol when given in combination with its most commonly used antidote, acetylcysteine.
Limitation of Availability
Limiting the availability of paracetamol tablets has been attempted in some countries. In the UK, sales of over-the-counter paracetamol are restricted to packs of 32 500 mg tablets in pharmacies, and 16 500 mg tablets in non-pharmacy outlets. Pharmacists may provide up to 100 tablets for those with chronic conditions at the pharmacist's discretion. In Ireland, the limits are 24 and 12 tablets, respectively. Subsequent study suggests that these interventions have had a significant effect in reducing poisoning deaths from paracetamol overdose.
One suggested method of prevention is to make paracetamol a prescription-only medicine, or to remove it entirely from the market. However, overdose is a relatively minor problem; for example, only 0.08% of the UK population present with paracetamol overdose each year. In contrast, paracetamol is a safe and effective medication that is taken without complications by millions of people. In addition, alternative pain relief medications such as aspirin are more toxic in overdose, whereas non-steroidal anti-inflammatory drugs are associated with more adverse effects following normal use.
Paracetamol ester prodrug with L-pyroglutamic acid (PCA), a biosynthetic precursors of glutathione, has been synthesized to reduce paracetamol hepatotoxicity and improve bioavailability. The toxicological studies of different paracetamol esters show that L-5-oxo-pyrrolidine-2-paracetamol carboxylate reduces toxicity after administration of an overdose of paracetamol to mice. The glutathione hepatic values in mice induced by intraperitoneal injection of the ester are superimposable with the GSH levels recorded in no-treated mice control group. The mice group treated with an equivalent dose of paracetamol showed a significative decrease of gluthathione of 35% (p<0.01 vs untreated control group). The oral LD50 was found to be greater than 2000 mg kg-1, whereas the intraperitoneal LD50 was 1900 mg kg-1. These results taken together with the good hydrolysis and bioavailability data show that this ester is a potential candidate as a prodrug of paracetamol.
Reducing publicity about paracetamol and the inclusion of warnings on packs of paracetamol have also been suggested as strategies to reduce overdose.
In adults, the initial treatment for paracetamol overdose is gastrointestinal decontamination. Paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this timeframe. Gastric lavage, better known as stomach pumping, may be considered if the amount ingested is potentially life-threatening and the procedure can be performed within 60 minutes of ingestion. Activated charcoal is the most common gastrointestinal decontamination procedure as it adsorbs paracetamol, reducing its gastrointestinal absorption. Administering activated charcoal also poses less risk of aspiration than gastric lavage.
It appears that the most benefit from activated charcoal is gained if it is given within 30 minutes to two hours of ingestion. Administering activated charcoal later than 2 hours can be considered in patients that may have delayed gastric emptying due to co-ingested drugs or following ingestion of sustained- or delayed-release paracetamol preparations. Activated charcoal should also be administered if co-ingested drugs warrant decontamination. There was reluctance to give activated charcoal in paracetamol overdose, because of the concern that it may also absorb the oral antidote acetylcysteine. Studies have shown that 39% less acetylcysteine is absorbed into the body when they are administered together. There are conflicting recommendations regarding whether to change the dosing of oral acetylcysteine after the administration of activated charcoal, and even whether the dosing of acetylcysteine needs to be altered at all. Intravenous acetylcystine has no interaction with activated charcoal.
Inducing vomiting with syrup of ipecac has no role in paracetamol overdose because the vomiting it induces delays the effective administration of activated charcoal and oral acetylcysteine. Liver injury is extremely rare after acute accidental ingestion in children under 6 years of age. Children with accidental exposures do not require gastrointestinal decontamination with either gastric lavage, activated charcoal, or syrup of ipecac.
Acetylcysteine, also called N-acetylcysteine or NAC, works to reduce paracetamol toxicity by replenishing body stores of the antioxidant glutathione. Glutathione react with the toxic NAPQI metabolite so that it does not damage cells and can be safely excreted. NAC was usually given following a treatment nomogram (one for patients with risk factors, and one for those without) but the use of nomogram is no longer recommended as evidence base 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 certaininy in clinical practice. Cysteamine and methionine have also been used to prevent hepatotoxicity, although studies show that both are associated with more adverse effects than acetylcysteine. Additionally, acetylcysteine has been shown to be a more effective antidote, particularly in patients presenting greater than 8 hours post-ingestion.
If the patient presents less than eight hours after paracetamol overdose, then acetylcysteine significantly reduces the risk of serious hepatotoxicity and guarantees survival. If acetylcysteine is started more than 8 hours after ingestion, there is a sharp decline in its effectiveness because the cascade of toxic events in the liver has already begun, and the risk of acute hepatic necrosis and death increases dramatically. Although acetylcysteine is most effective if given early, it still has beneficial effects if given as late as 48 hours after ingestion. In clinical practice, if the patient presents more than eight hours after the paracetamol overdose, then activated charcoal is not useful, and acetylcysteine is started immediately. In earlier presentations, charcoal can be given when the patient arrives and acetylcysteine is initiated while waiting for the paracetamol level results to return from the laboratory.
In United States practice, intravenous (IV) and oral administration are considered to be equally effective if given within 8 hours of ingestion. However, IV is the only recommended route in Australasian and British practice. Oral acetylcysteine is given as a 140 mg/kg loading dose followed by 70 mg/kg every four hours for 17 more doses. Oral acetylcysteine may be poorly tolerated due to its unpleasant taste, odor, and its tendency to cause nausea and vomiting. If repeat doses of charcoal are indicated because of another ingested drug, then subsequent doses of charcoal and acetylcysteine should be staggered.
Intravenous acetylcysteine is given as a continuous infusion over 20 hours for a total dose 300 mg/kg. Recommended administration involves infusion of a 150 mg/kg loading dose over 15 to 60 minutes, followed by a 50 mg/kg infusion over four hours; the last 100 mg/kg are infused over the remaining 16 hours of the protocol. Intravenous acetylcysteine has the advantage of shortening hospital stay, increasing both doctor and patient convenience, and allowing administration of activated charcoal to reduce absorption of both the paracetamol and any co-ingested drugs without concerns about interference with oral acetylcysteine.
The most common adverse effect to acetylcysteine treatment is an anaphylactoid reaction, usually manifested by rash, wheeze, or mild hypotension. Adverse reactions are more common in people treated with IV acetylcysteine, occurring in 4 to 23% of patients. Rarely, severe life-threatening reactions may occur in predisposed individuals, such as patients with asthma. If an anaphylactoid reaction occurs the acetylcysteine is temporarily halted or slowed and antihistamines and other supportive care is administered.
In patients who develop fulminant hepatic failure or who are otherwise expected to die from liver failure, the mainstay of management is liver transplantation. Liver transplants are performed in specialist centers. The most commonly used criteria for liver transplant was developed by physicians at King's College Hospital in London. Patients are recommended for transplant if they have an arterial blood pH less than 7.3 after fluid resuscitation or if a patient has Grade III or IV encephalopathy, a prothrombin time greater than 100 seconds, and a serum creatinine greater than 300 mmol/L In a 24 hour period. Other forms of liver support have been used including partial liver transplants. These techniques have the advantage of supporting the patient while their own liver regenerates. Once liver function returns immunosuppressive drugs are discontinued and they avoid taking immunosuppressive medication for the rest of their lives.
The mortality rate from paracetamol overdose increases two days after the ingestion, reaches a maximum on day four, and then gradually decreases. Acidemia is the most important single indicator of probable mortality and the need for transplantation. A mortality rate of 95% without transplant was reported in patients who had a documented pH less than 7.30. Other indicators of poor prognosis include renal insufficiency, grade 3 or worse hepatic encephalopathy, a markedly elevated prothrombin time, or an elevated blood lactic acid level. One study has shown that a factor V level less than 10% of normal indicated a poor prognosis (91% mortality), whereas a ratio of factor VIII to factor V of less than 30 indicated a good prognosis (100% survival). Patients with a poor prognosis are usually identified for likely liver transplantation. Patients that do not die are expected to fully recover and have a normal life expectancy and quality of life.
Paracetamol is contained in many preparations, available as both over-the-counter and as prescription-only medications. Because of its wide availability paired with comparably high toxicity, (compared to ibuprofen and aspirin) there is a much higher potential for overdose. Paracetamol toxicity is one of the most common causes of poisoning worldwide. In the United States, the United Kingdom, Australia, and New Zealand, paracetamol is the most common cause of drug overdoses. Additionally, in both the United States and the United Kingdom it is the most common cause of acute liver failure.
In England and Wales an estimated 41,200 cases of paracetamol poisoning occurred in 1989 to 1990, with a mortality of 0.40%. It is estimated that 150 to 200 deaths and 15 to 20 liver transplants occur as a result of poisoning each year in England and Wales. Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance, accounting for more than 100,000 calls, as well as 56,000 emergency room visits, 2,600 hospitalizations, and 458 deaths due to acute liver failure per year. A study of cases of acute liver failure between November 2000 and October 2004 by the Centers for Disease Control and Prevention in the USA found that paracetamol was the cause of 41% of all cases in adults, and 25% of cases in children.
- Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiødt FV, Ostapowicz G, Shakil AO, Lee WM; Acute Liver Failure Study Group. (December 2005). "Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study". Hepatology (Baltimore, Md.) 42 (6): 1364–72. doi:10.1002/hep.20948. PMID 16317692.
- Ryder SD, Beckingham IJ (February 2001). "Other causes of parenchymal liver disease". BMJ (Clinical research ed.) 322 (7281): 290–2. doi:10.1136/bmj.322.7281.290. PMC 1119531. PMID 11157536.
- Metabolism of acetaminophen (paracetamol), acetanilide and phenacetin
- Dart RC, Erdman AR, Olson KR, Christianson G, Manoguerra AS, Chyka PA, Caravati EM, Wax PM, Keyes DC, Woolf AD, Scharman EJ, Booze LL, Troutman WG; American Association of Poison Control Centers (2006). "Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management". Clinical toxicology (Philadelphia, Pa.) 44 (1): 1–18. doi:10.1080/15563650500394571. PMID 16496488.
- Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA (March 2008). "Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres". The Medical journal of Australia 188 (5): 296–301. PMID 18312195.
- Watkins PB, Kaplowitz N, Slattery JT, et al. (July 2006). "Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial". JAMA: the Journal of the American Medical Association 296 (1): 87–93. doi:10.1001/jama.296.1.87. PMID 16820551.
- Dart RC, Bailey E (2007). "Does therapeutic use of acetaminophen cause acute liver failure?". Pharmacotherapy 27 (9): 1219–30. doi:10.1592/phco.27.9.1219. PMID 17723075.
- Daly FF, O'Malley GF, Heard K, Bogdan GM, Dart RC (October 2004). "Prospective evaluation of repeated supratherapeutic acetaminophen (paracetamol) ingestion". Annals of Emergency Medicine 44 (4): 393–8. doi:10.1016/j.annemergmed.2004.05.005. PMID 15459622.
- Tenenbein M (2004). "Acetaminophen: the 150 mg/kg myth". Journal of toxicology. Clinical toxicology 42 (2): 145–8. doi:10.1081/CLT-120030939. PMID 15214618.
- "Father claims overdose medics 'killed his daughter'". BBC News. February 4, 2011.
- Vuppalanchi R, Liangpunsakul S, Chalasani N (March 2007). "Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States?". Am. J. Gastroenterol. 102 (3): 558–62; quiz 693. doi:10.1111/j.1572-0241.2006.01019.x. PMID 17156142.
- Rumack B, Matthew H (1975). "Acetaminophen poisoning and toxicity". Pediatrics 55 (6): 871–76. PMID 1134886.
- Zezulka A, Wright N (September 1982). "Severe metabolic acidosis early in paracetamol poisoning". British medical journal (Clinical research ed.) 285 (6345): 851–2. doi:10.1136/bmj.285.6345.851. PMC 1499688. PMID 6811039.
- Roth B, Woo O, Blanc P (April 1999). "Early metabolic acidosis and coma after acetaminophen ingestion". Annals of Emergency Medicine 33 (4): 452–6. doi:10.1016/S0196-0644(99)70312-4. PMID 10092726.
- Heard KJ (July 2008). "Acetylcysteine for Acetaminophen Poisoning". The New England Journal of Medicine 359 (3): 285–92. doi:10.1056/NEJMct0708278. PMC 2637612. PMID 18635433.
- Boutis K, Shannon M (2001). "Nephrotoxicity after acute severe acetaminophen poisoning in adolescents". Journal of toxicology. Clinical toxicology 39 (5): 441–5. doi:10.1081/CLT-100105413. PMID 11545233.
- Linden CH, Rumack BH (February 1984). "Acetaminophen overdose". Emergency medicine clinics of North America 2 (1): 103–19. PMID 6394298.
- Richardson, JA (July–September 2000). "Management of acetaminophen and ibuprofen toxicoses in dogs and cats". Journal of Veterinary Emergency and Critical Care 10 (4): 285–291. doi:10.1111/j.1476-4431.2000.tb00013.x.
- Rumbeiha WK, Lin YS, Oehme FW (November 1995). "Comparison of N-acetylcysteine and methylene blue, alone or in combination, for treatment of acetaminophen toxicosis in cats". American journal of veterinary research 56 (11): 1529–33. PMID 8585668.
- Corcoran GB, Mitchell JR, Vaishnav YN, Horning EC (November 1980). "Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-p-benzoquinoneimine". Molecular Pharmacology 18 (3): 536–42. PMID 7464816.
- Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB (October 1973). "Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione". The Journal of Pharmacology and Experimental Therapeutics 187 (1): 211–7. PMID 4746329.
- Dai Y, Cederbaum AI (June 1995). "Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells". The Journal of Pharmacology and Experimental Therapeutics 273 (3): 1497–505. PMID 7791125.
- Zimmerman HJ, Maddrey WC (1995). "Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure". Hepatology 22 (3): 767–73. doi:10.1002/hep.1840220312. PMID 7657281.
- Dargan PI, Jones AL (2002). "Should a lower treatment line be used when treating paracetamol poisoning in patients with chronic alcoholism?: a case against". Drug safety : an international journal of medical toxicology and drug experience 25 (9): 625–32. PMID 12137557.
- Buckley NA, Srinivasan J (2002). "Should a lower treatment line be used when treating paracetamol poisoning in patients with chronic alcoholism?: a case for". Drug safety : an international journal of medical toxicology and drug experience 25 (9): 619–24. PMID 12137556.
- Schmidt LE, Dalhoff K, Poulsen HE (April 2002). "Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity". Hepatology 35 (4): 876–82. doi:10.1053/jhep.2002.32148. PMID 11915034.
- Crippin JS (April 1993). "Acetaminophen hepatotoxicity: potentiation by isoniazid". The American journal of gastroenterology 88 (4): 590–2. PMID 8470644.
- Nolan CM, Sandblom RE, Thummel KE, Slattery JT, Nelson SD (1994). "Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis". Chest 105 (2): 408–11. doi:10.1378/chest.105.2.408. PMID 7508362.
- Bray GP, Harrison PM, O'Grady JG, Tredger JM, Williams R (July 1992). "Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure". Human & Experimental Toxicology 11 (4): 265–70. doi:10.1177/096032719201100405. PMID 1354974.
- Farrell, Susan E (October 3, 2007). "Toxicity, Acetaminophen". emedicine. Retrieved November 9, 2008.
- Bartlett D (June 2004). "Acetaminophen toxicity". Journal of emergency nursing: JEN : official publication of the Emergency Department Nurses Association 30 (3): 281–3. doi:10.1016/j.jen.2004.01.023. PMID 15192687.
- Jones AL (March 2000). "Recent advances in the management of late paracetamol poisoning". Emergency medicine Australasia 12 (1): 14–21. doi:10.1046/j.1442-2026.2000.00088.x.
- Shihana F, Dissanayake D, Dargan P, Dawson A. A modified low-cost colorimetric method for paracetamol (acetaminophen) measurement in plasma. Clin Toxicol 48: 42-46, 2010.
- R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 9-12.
- Dargan PI, Jones AL (April 2003). "Management of paracetamol poisoning". Trends in pharmacological sciences 24 (4): 154–7. doi:10.1016/S0165-6147(03)00053-1. PMID 12706999.
- Heptonstall JP (April 2006). "Time to make paracetamol with methionine available". BMJ (Clinical research ed.) 332 (7544): 795. doi:10.1136/bmj.332.7544.795-b. PMC 1420701. PMID 16575097.
- Chang, Matthew. "Acetaminophen in Combination With N-Acetylcysteine (NAC) Versus Placebo in Treating Fever". Retrieved 17 November 2012.
- Hughes B, Durran A, Langford NJ, Mutimer D (August 2003). "Paracetamol poisoning—impact of pack size restrictions". Journal of clinical pharmacy and therapeutics 28 (4): 307–10. doi:10.1046/j.1365-2710.2003.00497.x. PMID 12911683.
- Sheen CL, Dillon JF, Bateman DN, Simpson KJ, Macdonald TM (September 2002). "Paracetamol toxicity: epidemiology, prevention and costs to the health-care system". QJM : monthly journal of the Association of Physicians 95 (9): 609–19. doi:10.1093/qjmed/95.9.609. PMID 12205339.
- Laffoy M, Scallan E, Byrne G (2001). "Paracetamol availability and overdose in Ireland". Irish medical journal 94 (7): 212–4. PMID 11693213.
- BMJ 2013;346:f403, http://www.bmj.com/content/346/bmj.f403
- Jones A (2002). "Over-the-counter analgesics: a toxicology perspective". Am J Ther 9 (3): 245–57. doi:10.1097/00045391-200205000-00010. PMID 11941384.
- Bousquet E, Marrazzo A, Puglisi G, Spadaro A (1996). "Synthesis, physical properties, toxicological studies and bioavailability of L-pyroglutamic and L-glutamic acid esters of paracetamol as potentially useful prodrugs". J Pharm Pharmacol 48 (5): 479–85. doi:10.1111/j.2042-7158.1996.tb05958.x. PMID 8799871.
- Vale JA, Kulig K; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists (2004). "Position paper: gastric lavage". Journal of toxicology. Clinical toxicology 42 (7): 933–43. doi:10.1081/CLT-200045006. PMID 15641639.
- Spiller HA, Sawyer TS (August 2007). "Impact of activated charcoal after acute acetaminophen overdoses treated with N-acetylcysteine". The Journal of emergency medicine 33 (2): 141–4. doi:10.1016/j.jemermed.2007.02.016. PMID 17692765.
- Buckley NA, Whyte IM, O'Connell DL, Dawson AH (1999). "Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose". Journal of toxicology. Clinical toxicology 37 (6): 753–7. doi:10.1081/CLT-100102452. PMID 10584587.
- Isbister G, Whyte I, Dawson A (2001). "Pediatric acetaminophen overdose". Journal of toxicology. Clinical toxicology 39 (2): 169–72. doi:10.1081/CLT-100103834. PMID 11407504.
- Buckley NA, Whyte IM, O'Connell DL, Dawson AH (1999). "Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose". Journal of toxicology. Clinical toxicology 37 (6): 753–7. doi:10.1081/CLT-100102452. PMID 10584587.
- Renzi FP, Donovan JW, Martin TG, Morgan L, Harrison EF (June 1985). "Concomitant use of activated charcoal and N-acetylcysteine". Annals of Emergency Medicine 14 (6): 568–72. doi:10.1016/S0196-0644(85)80781-2. PMID 3994080.
- Ekins BR, Ford DC, Thompson MI, Bridges RR, Rollins DE, Jenkins RD (November 1987). "The effect of activated charcoal on N-acetylcysteine absorption in normal subjects". The American journal of emergency medicine 5 (6): 483–7. doi:10.1016/0735-6757(87)90166-5. PMID 3663288.
- Spiller HA, Krenzelok EP, Grande GA, Safir EF, Diamond JJ (March 1994). "A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose". Annals of Emergency Medicine 23 (3): 519–23. doi:10.1016/S0196-0644(94)70071-0. PMID 8135427.
- Piperno E, Berssenbruegge DA (October 1976). "Reversal of experimental paracetamol toxicosis with N-acetylcysteine". Lancet 2 (7988): 738–9. doi:10.1016/S0140-6736(76)90030-1. PMID 61415.
- "Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine". Drug Safety Update (Medicines and Healthcare Products Regulatory Agency (MHRA)) 6 (2): A1. September 2012.
- Brok J, Buckley N, Gluud C (2006). "Interventions for paracetamol (acetaminophen) overdose". In Brok, Jesper. Cochrane database of systematic reviews (Online) (2): CD003328. doi:10.1002/14651858.CD003328.pub2. PMID 16625578.
- Mant TG, Tempowski JH, Volans GN, Talbot JC (July 1984). "Adverse reactions to acetylcysteine and effects of overdose". British medical journal (Clinical research ed.) 289 (6439): 217–9. doi:10.1136/bmj.289.6439.217. PMC 1442311. PMID 6234965.
- Alsalim W, Fadel M (July 2003). "Oral methionine compared with intravenous n-acetyl cysteine for paracetamol overdose". Emergency medicine journal : EMJ 20 (4): 366–7. doi:10.1136/emj.20.4.366. PMC 1726135. PMID 12835357.
- Keays R, Harrison P, Wendon J, Forbes A, Gove C, Alexander G, Williams R (1991). "Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial". BMJ 303 (6809): 1026–9. doi:10.1136/bmj.303.6809.1026. PMC 1671790. PMID 1954453.
- Kanter MZ (October 2006). "Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning". American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 63 (19): 1821–7. doi:10.2146/ajhp060050. PMID 16990628.
- Selvan VA, Calvert SH, Cavell G, Glucksman E, Kerins M, Gonzalez J (July 2007). "Weight‐based N‐acetylcysteine dosing chart to minimise the risk of calculation errors in prescribing and preparing N‐acetylcysteine infusions for adults presenting with paracetamol overdose in the emergency department". Emergency medicine journal : EMJ 24 (7): 482–4. doi:10.1136/emj.2006.043141. PMC 2796160. PMID 17582039.
- Woo OF, Mueller PD, Olson KR, Anderson IB, Kim SY (April 2000). "Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose". Annals of Emergency Medicine 35 (4): 363–8. doi:10.1016/S0196-0644(00)70055-2. PMID 10736123.
- Buckley N, Whyte I, O'Connell D, Dawson A (1999). "Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning?". Journal of toxicology. Clinical toxicology 37 (6): 759–67. doi:10.1081/CLT-100102453. PMID 10584588.
- Buckley N, Eddleston M (December 2005). "Paracetamol (acetaminophen) poisoning". Clinical evidence (14): 1738–44. PMID 16620471.
- Appelboam AV, Dargan PI, Knighton J (November 2002). "Fatal anaphylactoid reaction to N-acetylcysteine: caution in patients with asthma". Emergency medicine journal : EMJ 19 (6): 594–5. doi:10.1136/emj.19.6.594. PMC 1756296. PMID 12421803.
- Schmidt LE, Dalhoff K (January 2001). "Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning". British Journal of Clinical Pharmacology 51 (1): 87–91. doi:10.1046/j.1365-2125.2001.01305.x. PMC 2014432. PMID 11167669.
- Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT (August 1977). "Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine". Lancet 2 (8035): 432–4. doi:10.1016/S0140-6736(77)90612-2. PMID 70646.
- Bailey B, McGuigan MA (June 1998). "Management of anaphylactoid reactions to intravenous N-acetylcysteine". Annals of Emergency Medicine 31 (6): 710–5. doi:10.1016/S0196-0644(98)70229-X. PMID 9624310.
- O'Grady JG, Alexander GJ, Hayllar KM, Williams R (August 1989). "Early indicators of prognosis in fulminant hepatic failure". Gastroenterology 97 (2): 439–45. PMID 2490426.
- Jaeck D, Boudjema K, Audet M, Chenard-Neu MP, Simeoni U, Meyer C, Nakano H, Wolf P (2002). "Auxiliary partial orthotopic liver transplantation (APOLT) in the treatment of acute liver failure". Journal of gastroenterology. 37 Suppl 13: 88–91. doi:10.1007/BF02990107. PMID 12109674.
- Lodge JP, Dasgupta D, Prasad KR, Attia M, Toogood GJ, Davies M, Millson C, Breslin N, Wyatt J, Robinson PJ, Bellamy MC, Snook N, Pollard SG (February 2008). "Emergency subtotal hepatectomy: a new concept for acetaminophen-induced acute liver failure: temporary hepatic support by auxiliary orthotopic liver transplantation enables long-term success". Annals of surgery 247 (2): 238–49. doi:10.1097/SLA.0b013e31816401ec. PMID 18216528.
- Bernal W, Donaldson N, Wyncoll D, Wendon J (February 2002). "Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study". Lancet 359 (9306): 558–63. doi:10.1016/S0140-6736(02)07743-7. PMID 11867109.
- Pereira LM, Langley PG, Hayllar KM, Tredger JM, Williams R (1992). "Coagulation factor V and VIII/V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: relation to other prognostic indicators". Gut 33 (1): 98–102. doi:10.1136/gut.33.1.98. PMC 1373872. PMID 1740285.
- Ding GK, Buckley NA (September 2008). "Evidence and consequences of spectrum bias in studies of criteria for liver transplant in paracetamol hepatotoxicity". QJM : monthly journal of the Association of Physicians 101 (9): 723–9. doi:10.1093/qjmed/hcn077. PMID 18606611.
- Sheen C, Dillon J, Bateman D, Simpson K, Macdonald T (2002). "Paracetamol toxicity: epidemiology, prevention and costs to the health-care system". QJM : monthly journal of the Association of Physicians 95 (9): 609–19. doi:10.1093/qjmed/95.9.609. PMID 12205339.
- Gunnell D, Murray V, Hawton K (2000). "Use of paracetamol (acetaminophen) for suicide and nonfatal poisoning: worldwide patterns of use and misuse". Suicide & life-threatening behavior 30 (4): 313–26. PMID 11210057.
- Hawkins LC, Edwards JN, Dargan PI (2007). "Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature". Drug safety : an international journal of medical toxicology and drug experience 30 (6): 465–79. doi:10.2165/00002018-200730060-00002. PMID 17536874.
- Khashab M, Tector AJ, Kwo PY (March 2007). "Epidemiology of acute liver failure". Current gastroenterology reports 9 (1): 66–73. doi:10.1007/s11894-008-0023-x. PMID 17335680.
- Lee WM (July 2004). "Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure". Hepatology 40 (1): 6–9. doi:10.1002/hep.20293. PMID 15239078.
- Bower WA, Johns M, Margolis HS, Williams IT, Bell BP (November 2007). "Population-based surveillance for acute liver failure". The American journal of gastroenterology 102 (11): 2459–63. doi:10.1111/j.1572-0241.2007.01388.x. PMID 17608778.
- "Use Only as Directed". This American Life. Episode 505. 20 September 2013. Public Radio International. WBEZ. http://www.thisamericanlife.org/radio-archives/episode/505/use-only-as-directed. Retrieved 24 September 2013.
- Gerth, Jeff; T. Christian Miller (20 September 2013). "Use Only as Directed". ProPublica. Retrieved 12 October 2013.
- Miller, T. Christian; Jeff Gerth (20 September 2013). "Dose of Confusion". ProPublica. Retrieved 12 October 2013.</ref>