paracetamol
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Paracetamol, also known as acetaminophen, is a
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmacotherapy) is an imp ...
used to treat
fever Fever, also referred to as pyrexia, is defined as having a temperature Temperature is a physical quantity that expresses quantitatively the perceptions of hotness and coldness. Temperature is measurement, measured with a thermometer. Th ...
and mild to moderate
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferior to
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes dysmenorrhea, painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a paten ...
in that respect, and the benefits of its use for fever are unclear. Paracetamol may relieve pain in acute mild
migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...
but only slightly in episodic
tension headache Tension headache, also known as stress headache, or tension-type headache (TTH), is the most common type of primary headache. The pain can radiate from the lower back of the head, the neck, eyes or other muscle groups in the body typically affecti ...
. However, the
aspirin/paracetamol/caffeine Aspirin(acetylsalicylic acid) / paracetamol(acetaminophen) / caffeine is a combination drug for the treatment of pain, especially tension headache and migraine. It is sold in the US under the trade names Goody's Powder and Excedrin (brand), Exced ...
combination helps with both conditions where the pain is mild and is recommended as a
first-line treatment A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health Health, according to the World Health Organization, is "a state of complete physical, Mental health, mental and social well-being and ...
for them. Paracetamol is effective for post-
surgical Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pa ...
pain, but it is inferior to ibuprofen. The paracetamol/ibuprofen combination provides further increase in potency and is superior to either
drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inh ...
alone. The pain relief paracetamol provides in
osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of articular cartilage, joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of ...
is small and clinically insignificant. The evidence in its favor for the use in low back pain,
cancer pain Pain in cancer may arise from a tumor compressing or infiltrating nearby body parts; from treatments and diagnostic procedures; or from skin, nerve and other changes caused by a hormone imbalance or immune response. Most Chronic pain, chronic (long ...
, and
neuropathic pain Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous ...
is insufficient. In the short term, paracetamol is safe and effective when used as directed. Short term adverse effects are uncommon and similar to ibuprofen, but paracetamol is typically safer than NSAIDs for long term use. Paracetamol is also often used in patients who cannot tolerate NSAIDs like
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes dysmenorrhea, painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a paten ...
. Chronic consumption of paracetamol may result in a drop in
hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
level, indicating possible
gastrointestinal bleeding Gastrointestinal bleeding (GI bleed), also called gastrointestinal hemorrhage (GIB), is all forms of bleeding in the gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of ...
, and abnormal liver function tests. Some epidemiological studies have linked paracetamol to cardiovascular, renal, and gastrointestinal diseases, but are largely due to confounding biases and is of insignificant relevance with short-term use of paracetamol. Paracetamol may slightly increase systolic blood pressure in hypertensive patients at a dose of 4 grams a day. Elevated frequency of
asthma Asthma is a chronic (medicine), long-term inflammation, inflammatory disease of the bronchi, airways of the lungs. It is characterized by variable and recurring symptoms, reversible Airway obstruction, airflow obstruction, and easily triggered ...
and developmental and reproductive disorders is observed in the offspring of women with prolonged use of paracetamol during
pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...
, although whether paracetamol is the true cause of this increase is unclear. Some studies suggest that there is evidence for the association between paracetamol during pregnancy and
autism spectrum disorder The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
and
attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise Development ...
, while making clear further research is required to establish any causal link, which has prompted some calls to limit its use in pregnancy to the lowest effective dosage for the shortest possible time. The recommended maximum daily dose for an adult is three to four grams. Higher doses may lead to toxicity, including liver failure. Paracetamol poisoning is the foremost cause of
acute liver failure Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complicati ...
in the
Western world The Western world, also known as the West, primarily refers to the various nations and state (polity), states in the regions of Europe, North America, and Oceania.
, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. Paracetamol was first made in 1877 or possibly 1852. It is the most commonly used medication for pain and fever in both the United States and Europe. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
. Paracetamol is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
, with brand names including Tylenol and Panadol among others. In 2020, it was the 118th most commonly prescribed medication in the United States, with more than 5million prescriptions.


Medical uses


Fever

Paracetamol is a drug of choice for reducing
fever Fever, also referred to as pyrexia, is defined as having a temperature Temperature is a physical quantity that expresses quantitatively the perceptions of hotness and coldness. Temperature is measurement, measured with a thermometer. Th ...
. However, there has been a lack of research on its
antipyretic An antipyretic (, from ''anti-'' 'against' and ' 'feverish') is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in Thermoregulation, temperature. The body then works to lower the te ...
properties, particularly in adults. The most recent review on paracetamol and management of fever in the general practice (2008) argued that its benefits are unclear. Additionally, when taken for the common cold paracetamol may relieve stuffed or runny nose but not other cold symptoms such as sore throat, malaise, sneezing and cough; this data, however, is of low quality. For patients in critical care, paracetamol decreased body temperature by only 0.20.3°C more than control interventions; there was no difference in mortality. It did not change the outcome in febrile patients with stroke. The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported. Paracetamol offered no benefit in the treatment of
dengue fever Dengue fever is a mosquito-borne tropical disease caused by the dengue virus ''Dengue virus'' (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family ''Flaviviridae''; genus ''Flavivi ...
and was accompanied by a higher rate of liver enzyme elevation: a sign of a potential liver damage. Overall, there is no support for a routine administration of
antipyretic An antipyretic (, from ''anti-'' 'against' and ' 'feverish') is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in Thermoregulation, temperature. The body then works to lower the te ...
drugs, including paracetamol, to hospitalized patients with fever and infection. The efficacy of paracetamol in children with fever is unclear. Paracetamol should not be used solely with the aim of reducing body temperature; however, it may be considered for children with fever who appear distressed. It does not prevent febrile seizures and should not be used for that purpose. 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 emergency situations. Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7°C. Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis), including children younger than 2 years old, with equivalent safety. Exacerbation of asthma occurs with similar frequency for both medications. Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended, however doses may be alternated if required.


Pain

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
dysmenorrhea Dysmenorrhea, also known as period pain, painful periods or menstrual cramps, is pain during menstruation. Its usual onset occurs around the time that menstruation begins. Symptoms typically last less than three days. The pain is usually in the ...
. It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient.


Musculoskeletal pain

The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain. It appears to provide only small and not clinically important benefits in
osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of articular cartilage, joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of ...
.
American College of Rheumatology The American College of Rheumatology (ACR; until 1985 called American Rheumatism Association) is an organization of and for physicians, health professionals, and scientists that advances rheumatology Rheumatology (Greek ''ῥεῦμα'', ''rheû ...
and Arthritis Foundation guideline for the management of osteoarthritis notes that the
effect size In statistics Statistics (from German language, German: ''wikt:Statistik#German, Statistik'', "description of a State (polity), state, a country") is the discipline that concerns the collection, organization, analysis, interpretation, an ...
in
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s of paracetamol has been very small, which suggests that for most individuals it is ineffective. The guideline conditionally recommends paracetamol for short-term and episodic use to those who do not tolerate
nonsteroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces pain, Anti-inflammatory, decreases inflammation, Antipyretic, decreases fever, and Antithrombotic, prevents blo ...
s. For people taking it regularly, monitoring for liver toxicity is required. Essentially the same recommendation was issued by EULAR for hand osteoarthritis. Similarly, European algorithm ESCEO for the treatment of knee osteoarthritis recommends limiting the of use paracetamol to short-term rescue analgesia only. Paracetamol is ineffective for acute low back pain. No randomized clinical trials evaluated its use for chronic or radicular back pain, and the evidence in favor of paracetamol is lacking.


Headaches

Paracetamol is effective for acute
migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...
: 39% of people experience pain relief at one hour compared with 20% in the control group. The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a
first-line treatment A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health Health, according to the World Health Organization, is "a state of complete physical, Mental health, mental and social well-being and ...
for migraine." The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend the combination as a "highlighted" one for self-medication of migraine, and paracetamol alone as a first choice. Paracetamol on its own only slightly alleviates episodic
tension headache Tension headache, also known as stress headache, or tension-type headache (TTH), is the most common type of primary headache. The pain can radiate from the lower back of the head, the neck, eyes or other muscle groups in the body typically affecti ...
in those who have them frequently. However, the
aspirin/paracetamol/caffeine Aspirin(acetylsalicylic acid) / paracetamol(acetaminophen) / caffeine is a combination drug for the treatment of pain, especially tension headache and migraine. It is sold in the US under the trade names Goody's Powder and Excedrin (brand), Exced ...
combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: 2 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. 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".


Dental and other post-surgical pain

Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain. For the relief of such pain, paracetamol is inferior to ibuprofen. Full therapeutic doses of
non-steroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class A drug class is a set of medications and other compounds that have a similar chemical structures, the same mechanism of action (i.e. binding to the same bi ...
s (NSAIDs) ibuprofen,
naproxen Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, gout and fever. It is Oral administration, taken orally. It is available in immediate and delay ...
or
diclofenac Diclofenac, sold under the brand name Voltaren, among others, is a nonsteroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces p ...
are clearly more efficacious than the paracetamol/codeine combination which is frequently prescribed for dental pain. The combinations of paracetamol and NSAIDs ibuprofen or
diclofenac Diclofenac, sold under the brand name Voltaren, among others, is a nonsteroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces p ...
are promising, possibly offering better pain control than either paracetamol or the NSAID alone. Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations. 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 A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...
helped only 7%.


Other pain

Paracetamol fails to relieve procedural pain in newborn babies. For perineal pain postpartum paracetamol appears to be less effective than
non-steroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class A drug class is a set of medications and other compounds that have a similar chemical structures, the same mechanism of action (i.e. binding to the same bi ...
s (NSAIDs). The studies to support or refute the use of paracetamol for cancer pain and for neuropathic pain are lacking. There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department. The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain.


Patent ductus arteriosus

Paracetamol helps ductal closure in patent ductus arteriosus. It is as effective for this purpose as ibuprofen or indomethacin, but results in a less frequent gastrointestinal bleeding than ibuprofen.


Adverse effects

Gastrointestinal adverse effects such as nausea and
abdominal pain Abdominal pain, also known as a stomach ache, is a symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an disease, illness, injury, or condition. A sign for example may be a higher or lower temperat ...
are common, and their frequency is similar to that of ibuprofen. Increase in risk-taking behavior is possible. According to the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
, the drug may cause rare and possibly fatal skin reactions such as
Stevens–Johnson syndrome Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome#Classification, Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of dise ...
and
toxic epidermal necrolysis Toxic epidermal necrolysis (TEN) is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and flu-like symptoms. A few days later th ...
, although an analysis of the French Pharmacovigilance Database indicated no obvious risk of these reactions. In clinical trials for
osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of articular cartilage, joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of ...
, the number of participants reporting adverse effects were similar for those on paracetamol and on
placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...
. 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. After 13 weeks of paracetamol therapy for knee pain, a drop in
hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
level indicating
gastrointestinal bleeding Gastrointestinal bleeding (GI bleed), also called gastrointestinal hemorrhage (GIB), is all forms of bleeding in the gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of ...
was observed in 20% of participants, this rate being similar to ibuprofen group. Due to the absence of controlled studies, most of the information about the long-term safety of paracetamol comes from
observational studies In fields such as epidemiology, social sciences, psychology and statistics, an observational study draws inferences from a sample (statistics), sample to a statistical population, population where the dependent and independent variables, independ ...
. These indicate a consistent pattern of increased mortality as well as
cardiovascular The blood circulatory system is a system of organs that includes the heart The heart is a muscular organ Organ may refer to: Biology * Organ (biology), a part of an organism Musical instruments * Organ (music), a family of keybo ...
(
stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
,
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Hemodynamics, blood flow decreases or stops to the coronary artery of the heart, causing ischemia, damage to the cardiac muscle, heart muscle. The most common symptom i ...
), gastrointestinal ( ulcers,
bleeding Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur Internal bleeding, internally, or externally either through a natural opening such as the Mouth (human) ...
) and
renal The kidneys are two reddish-brown bean-shaped organs In biology, an organ is a collection of Tissue (biology), tissues joined in a structural unit to serve a common function. In the biological organization, hierarchy of life, an organ lies ...
adverse effects with increased dose of paracetamol. Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer. Those who take it regularly at a higher dose (more than 23g daily) are at much higher risk (3.63.7 times) of gastrointestinal bleeding and other bleeding events. Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23% and kidney cancer by 28%. Paracetamol is particularly dangerous to the liver in overdose, but even without overdose those who take this drug may develop
acute liver failure Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complicati ...
requiring
liver transplantation Liver transplantation or hepatic transplantation is the replacement of a Liver disease, diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for Cirrhosis, end-stage liver disease and ...
more frequently than the users of
nonsteroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces pain, Anti-inflammatory, decreases inflammation, Antipyretic, decreases fever, and Antithrombotic, prevents blo ...
s. Paracetamol slightly but significantly increases
blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
and heart rate. The majority of observational studies suggests that, used chronically, it may increase the risk of developing
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not ...
, as confirmed in a prospective randomized confirmed trial. The risk is higher with the higher dose. The association between paracetamol use and
asthma Asthma is a chronic (medicine), long-term inflammation, inflammatory disease of the bronchi, airways of the lungs. It is characterized by variable and recurring symptoms, reversible Airway obstruction, airflow obstruction, and easily triggered ...
in children has been a matter of controversy. However, the most recent research suggests that there is no association, and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer ibuprofen.


Use in pregnancy

Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or
birth defects A birth defect, also known as a congenital disorder, is an abnormal condition that is present at childbirth, birth regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellect ...
. However, indications exist of a possible increase of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy. Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood
asthma Asthma is a chronic (medicine), long-term inflammation, inflammatory disease of the bronchi, airways of the lungs. It is characterized by variable and recurring symptoms, reversible Airway obstruction, airflow obstruction, and easily triggered ...
, but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult. Paracetamol, in a small scale meta analysis was also associated with 2030% increase in
autism spectrum disorder The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
,
attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise Development ...
, hyperactivity symptoms, and
conduct disorder Conduct disorder (CD) is a mental disorder diagnosed in childhood or adolescence that presents itself through a repetitive and persistent pattern of behavior that includes theft, lies, physical violence that may lead to destruction, and reckles ...
, 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 there was potential bias in the findings. There is also an argument that the large number, consistency, and the robust designs of the studies provide a strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders. In animal experiments, paracetamol disrupts fetal
testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate The prostate is both an Male accessory gland ...
production, and several epidemiological studies linked
cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek Greek may refer to: Greece Anything of, from, or related to Greece, a country in Southern Europe: *Gree ...
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. 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.


Overdose

Overdose A drug overdose (overdose or OD) is the ingestion Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in a substance through the mouth into the gastrointestinal tract, such as through e ...
s of paracetamol, that is, taking more than the recommended maximum daily dose of paracetamol for healthy adults of three or four grams, can cause potentially fatal
liver damage Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the sig ...
.
Paracetamol toxicity Paracetamol poisoning, also known as acetaminophen poisoning, is caused by excessive use of the medication paracetamol (acetaminophen). Most people have few or non-specific symptoms in the first 24 hours following overdose. These include f ...
is the foremost cause of
acute liver failure Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complicati ...
in the
Western world The Western world, also known as the West, primarily refers to the various nations and state (polity), states in the regions of Europe, North America, and Oceania.
, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. Paracetamol overdose results in more calls to
poison control center A poison control center is a medical service that is able to provide immediate, free, and expert treatment advice and assistance over the telephone in case of exposure to poisonous or hazardous substances. Poison control centers answer questions ...
s in the US than overdose of any other pharmacological substance. According to the FDA, in the United States, "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year ererelated 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." Overdoses are frequently related to high-dose
recreational use Recreational drug use indicates the use of one or more psychoactive drugs to induce an altered state of consciousness either for pleasure or for some other casual purpose or pastime by modifying the perceptions and emotions of the user. When a ...
of prescription
opioids Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia Anesthesia is a state of controlled, temporary loss of sensation or awarene ...
, as these opioids are most often combined with paracetamol. The overdose risk may be heightened by frequent consumption of alcohol. Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or
non-specific symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an disease, illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormali ...
s. The first symptoms of overdose usually begin several hours after ingestion, with
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomiting, vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or b ...
,
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...
, sweating, and
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
as
acute liver failure Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complicati ...
starts. 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. Treatment is aimed at removing the paracetamol from the body and replenishing
glutathione Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important Cell (biology), cellular components caused by sources such as reactive oxygen species, free ...
.
Activated charcoal "Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016). Background In an interv ...
can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote,
acetylcysteine Acetylcysteine, also known as ''N''-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia Pneumonia is an Infla ...
(also called ''N''-acetylcysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to prevent or at least decrease the possible damage to the liver; a liver transplant is often required if damage to the liver becomes severe. NAC was usually given following a treatment
nomogram A nomogram (from Greek language, Greek , "law" and , "line"), also called a nomograph, alignment chart, or abac, is a graphical Analog computer, calculating device, a two-dimensional diagram designed to allow the approximate graphical computa ...
(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. Toxicity of paracetamol is due to its quinone metabolite
NAPQI NAPQI, also known as NAPBQI or ''N''-acetyl-''p''-benzoquinone imine, is a toxic byproduct produced during the Drug metabolism, xenobiotic metabolism of the analgesic paracetamol (acetaminophen). It is normally produced only in small amounts, and ...
and NAC also helps in neutralizing it.
Kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
is also a possible side effect.


Interactions

Prokinetic agents such as
metoclopramide Metoclopramide is a medication used for stomach and esophagus, esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with gastric emptying, emptying of the stomach in people with gastroparesis, delayed stoma ...
accelerate gastric emptying, shorten time (tmax) to paracetamol peak blood plasma concentration (Cmax), and increase Cmax. Medications slowing gastric emptying such as propantheline and
morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...
lengthen tmax and decrease Cmax. 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. There have been suspicions that cytochrome inducers may enhance the toxic pathway of paracetamol metabolism to
NAPQI NAPQI, also known as NAPBQI or ''N''-acetyl-''p''-benzoquinone imine, is a toxic byproduct produced during the Drug metabolism, xenobiotic metabolism of the analgesic paracetamol (acetaminophen). It is normally produced only in small amounts, and ...
(see Paracetamol#Pharmacokinetics). By and large, these suspicions have not been confirmed. Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for
phenobarbital Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
,
primidone Primidone, sold under various brand names, is a barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnoti ...
,
isoniazid Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the Tuberculosis management, treatment of tuberculosis. For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomyci ...
, and possibly
St John's wort ''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''. Possibly a hybrid between ''Hypericum maculatum, H. maculatum'' and ''Hypericum attenuatum, H. ...
. On the other hand, the anti-tuberculosis drug
isoniazid Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the Tuberculosis management, treatment of tuberculosis. For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomyci ...
cuts the formation of NAPQI by 70%. Ranitidine increased paracetamol
area under the curve In mathematics, an integral assigns numbers to Function (mathematics), functions in a way that describes Displacement (geometry), displacement, area, volume, and other concepts that arise by combining infinitesimal data. The process of finding ...
(AUC) 1.6-fold. AUC increases are also observed with nizatidine and cisapride. The effect is explained by these drugs inhibiting glucuronidation of paracetamol. Paracetamol raises plasma concentrations of ethinylestradiol by 22% by inhibiting its sulfation. Paracetamol increases Prothrombin time, INR during warfarin therapy and should be limited to no more than 2 g per week.


Pharmacology


Pharmacodynamics

Paracetamol appears to exert its effects through two mechanisms: the inhibition of cyclooxygenase and actions of its metabolite AM404. Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical
nonsteroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces pain, Anti-inflammatory, decreases inflammation, Antipyretic, decreases fever, and Antithrombotic, prevents blo ...
s (NSAIDs) that act by inhibiting COX-1 and COX-2 enzymes and especially similar to selective COX-2 inhibitors. Paracetamol inhibits prostaglandin synthesis by Reduction (chemistry), reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of arachidonic acid and Organic peroxide#Biology, peroxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight. The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the central nervous system and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding. The second mechanism centers on the paracetamol metabolite AM404. This metabolite has been detected in the brains of animals and cerebrospinal fluid of humans taking paracetamol. Apparently, it is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase. AM404 is a weak agonist of cannabinoid receptors Cannabinoid receptor type 1, CB1 and Cannabinoid receptor type 2, CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor. This and other research indicate that Endocannabinoid system, cannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol.


Pharmacokinetics

After being taken by mouth, paracetamol is rapidly absorbed from the small intestine, while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach emptying and absorption, but the total amount absorbed stays the same. 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. Paracetamol's bioavailability is dose-dependent: it increases from 63% for 500mg dose to 89% for 1000mg dose. Its plasma terminal elimination half-life is 1.92.5 hours, and volume of distribution is roughly 50L. Protein binding is negligible, except under the conditions of overdose, when it may reach 1521%. The concentration in serum after a typical dose of paracetamol usually peaks below 30μg/mL (200μmol/L). After 4 hours, the concentration is usually less than 10μg/mL (66μmol/L). Paracetamol is drug metabolism, metabolized primarily in the liver, mainly by glucuronidation and sulfation, and the products are then eliminated in the urine (see the Scheme on the right). Only 25% of the drug is excreted unchanged in the urine. Glucuronidation by UGT1A1 and UGT1A6 accounts for 5070% of the drug metabolism. Additional 2535% of paracetamol is converted to sulfate by sulfation enzymes SULT1A1, SULT1A3, and SULT1E1. A minor metabolic pathway (5-15%) of oxidation by cytochrome P450 enzymes, mainly by CYP2E1, forms a toxic metabolite known as
NAPQI NAPQI, also known as NAPBQI or ''N''-acetyl-''p''-benzoquinone imine, is a toxic byproduct produced during the Drug metabolism, xenobiotic metabolism of the analgesic paracetamol (acetaminophen). It is normally produced only in small amounts, and ...
(''N''-acetyl-''p''-benzoquinone imine). NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with
glutathione Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important Cell (biology), cellular components caused by sources such as reactive oxygen species, free ...
. 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 the large amount of formed NAPQI, and NAPQI binds to mitochondria proteins of the liver cells causing oxidative stress and toxicity. Yet another minor but important direction of metabolism is deacetylation of 12% of paracetamol to form p-Aminophenol, ''p''-aminophenol. ''p''-Aminophenol is then converted in the brain by fatty acid amide hydrolase into AM404, a compound that may be partially responsible for the analgesic action of paracetamol.


Chemistry


Synthesis


Classical methods

The classical methods for the production of paracetamol involve the acetylation of 4-aminophenol with acetic anhydride as the last step. They differ in how 4-aminophenol is prepared. In one method, nitration of phenol with nitric acid affords 4-nitrophenol, which is reduced to 4-aminophenol by hydrogenation over Raney nickel. In another method, nitrobenzene is reduced electrolysis, electrolytically giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by Tin(II) chloride, Tin(II) Chloride in absolute ethanol or ethyl acetate to produce a 91% yield of 4-aminophenol.


Celanese synthesis

An alternative industrial synthesis developed at Celanese involves direct acylation of phenol with acetic anhydride in the presence of hydrogen fluoride, conversion of the resulting ketone to a ketoxime with hydroxylamine, followed by the acid-catalyzed Beckmann rearrangement. :


Reactions

4-Aminophenol, ''4''-Aminophenol may be obtained by the amide hydrolysis of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, ''4''-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an indophenol dye under oxidization by air.


History

Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as
antipyretic An antipyretic (, from ''anti-'' 'against' and ' 'feverish') is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in Thermoregulation, temperature. The body then works to lower the te ...
properties, and was quickly introduced into medical practice under the name of Antifebrin by Cahn & Hepp in 1886. But its unacceptable toxic effectsthe most alarming being cyanosis due to methemoglobinemia, an increase of
hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
in its ferric [Fe3+] state, called methemoglobin, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissueprompted the search for less toxic aniline derivatives. Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852. Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of 4-Nitrophenol, ''p''-nitrophenol with tin in glacial acetic acid in 1877, but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans. In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative. Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company. 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. In 1947, David Lester (biochemist), David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia. In 1948, Bernard Brodie (biochemist), Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor. They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol. This led to a "rediscovery" of paracetamol. Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol, aspirin, and caffeine. Reports in 1951 of three users stricken with the blood disease agranulocytosis led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected. The following year, 1952, paracetamol returned to the US market as a prescription drug. In the United Kingdom, marketing of paracetamol began in 1956 by Sterling-Winthrop Co. as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers. In 1963, paracetamol was added to the ''British Pharmacopoeia'', and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents. Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of analgesic nephropathy and hematological toxicity. Available in the US Over-the-counter drug, without a prescription since 1955 (1960, according to another source) paracetamol has become a common household drug. In 1988, Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994. 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 1000mg to 650mg, 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. In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325mg 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. Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325mg per dosage unit. In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children. In September 2013, "Use Only as Directed", an episode of the radio program ''This American Life'' highlighted deaths from paracetamol overdose. This report was followed by two reports by ProPublica alleging that the "FDA has long been aware of studies showing the risks of acetaminophen. So has the maker of Tylenol, McNeil Consumer Healthcare, a division of Johnson & Johnson" and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug." During the COVID-19 pandemic it was considered by some in the scientific community that it was an effective analgesic medication to treat symptoms of COVID-19, but this was found to be unsubstantiated.


Society and culture


Naming

''Paracetamol'' is the Australian Approved Name and British Approved Name as well as the international nonproprietary name used by the WHO and in many other countries; ''acetaminophen'' is the United States Adopted Name and Japanese Accepted Name and also the name generally used in Canada, Venezuela, Colombia, and Iran. Both ''paracetamol'' and ''acetaminophen'' are contractions of ''para''-acetylaminophenol, a chemical name for the compound. The initialism ''APAP'' used by dispensing pharmacists in the United States comes from the alternative chemical name [''N''-]acetyl-''para''-aminophenol.


Available forms

Paracetamol is available in oral, suppository, and intravenous forms. Intravenous paracetamol is sold under the brand name Ofirmev in the United States. In some formulations, paracetamol is combined with the opiate codeine, sometimes referred to as co-codamol (British Approved Name, BAN) and Panadeine in Australia. In the US, this combination is available only by prescription. As of 1 February 2018, medications containing codeine also became prescription-only in Australia. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (British Approved Name (BAN)), oxycodone or hydrocodone. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate. A combination of paracetamol, codeine, and the doxylamine, doxylamine succinate is also available. Paracetamol is sometimes combined with phenylephrine hydrochloride. Sometimes a third active ingredient, such as ascorbic acid, caffeine, Chlorphenamine, chlorpheniramine maleate, or guaifenesin is added to this combination.


Veterinary use


Cats

Paracetamol is extremely toxic to cats, which lack the necessary UGT1A6 enzyme to detoxify it. Initial symptoms include vomiting, salivation, and discoloration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, methemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation (methemoglobinemia and hemolytic anemia). Treatment of the toxicosis with N-acetylcysteine is recommended.


Dogs

Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs. A paracetamol-codeine product (brand name Pardale-V) licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person. It should be administered to dogs only on veterinary advice and with extreme caution. The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported. N-acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.


Snakes

Paracetamol is lethal to snakes, and has been suggested as a chemical control program for the invasive brown tree snake (''Boiga irregularis'') in Guam. Doses of 80mg are inserted into dead mice that are scattered by helicopter, as lethal bait to be consumed by the snakes.


Footnotes


References


External links

* * * {{Authority control Acetanilides Analgesics Antipyretics Novartis brands Drugs with unknown mechanisms of action Endocannabinoid reuptake inhibitors Haleon Hepatotoxins Pesticides Phenols World Health Organization essential medicines Wikipedia medicine articles ready to translate