Paracetamol
From Wikipedia, the free encyclopedia
Paracetamol (
// or
//), also known as
acetaminophen 
i//, or
APAP, chemically named N-acetyl-p-aminophenol, is a widely used
over-the-counter analgesic (pain reliever) and
antipyretic (fever reducer).
[7][8] Acetaminophen is the name adopted for this pharmacologic agent in the U.S. (
USAN) and Japan; paracetamol is approved in a variety of international venues (
INN,
AAN,
BAN, etc.).
[9][10][11] Common trade names in English-speaking markets are
Tylenol and
Panadol.
Paracetamol is classified as a mild analgesic. It is commonly used for the relief of
headaches and other minor aches and pains and is a major ingredient in numerous
cold and
flu remedies. In combination with
opioid analgesics, paracetamol can also be used in the management of more severe pain such as post-surgical pain and providing
palliative care in advanced cancer patients.
[12] Though paracetamol is used to treat inflammatory pain, it is not generally classified as an
NSAID because it exhibits only weak anti-inflammatory activity.
While generally safe for use at recommended doses, even small
overdoses can be fatal. Compared to other over-the-counter pain
relievers, paracetamol is significantly more toxic in overdose but may
be less toxic when used chronically at recommended doses.
[13] Paracetamol is the active metabolite of
phenacetin and
acetanilide, both once popular as analgesics and antipyretics in their own right.
[14][15] However, unlike phenacetin, acetanilide and their combinations, paracetamol is not considered
carcinogenic at therapeutic doses.
[16]
The words
acetaminophen (used in the United States,
[10] Canada,
[10] Japan)
[9] and
paracetamol (used elsewhere) both come from a chemical name for the compound:
para-
acetyl
aminophenol and
para-
acetyl
aminophen
ol.
In some contexts, such as on prescription bottles of painkillers that
incorporate this medicine, it is simply abbreviated as APAP, for
acetyl-
para-
amino
phenol. It is on the
World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic
health system.
[17]
Medical uses
Fever
Paracetamol is approved for reducing
fever in people of all ages.
[18] The
World Health Organization
(WHO) recommends that paracetamol only be used to treat fever in
children if their temperature is greater than 38.5 °C (101.3 °F).
[19] The efficacy of paracetamol by itself in children with fevers has been questioned
[20] and a meta-analysis showed that it is less effective than
ibuprofen.
[21]
Pain
Paracetamol is used for the relief of pains associated with many parts of the body. It has
analgesic properties comparable to those of
aspirin, while its anti-inflammatory effects are weaker. It is better tolerated than aspirin in patients in whom excessive
gastric acid secretion or prolongation of bleeding time may be a concern. Available without a prescription since 1959,
[22] it has since become a common household drug.
[23]
Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as the
NSAIDs
aspirin and ibuprofen, but ibuprofen and paracetamol have similar
effects in the treatment of headache. Paracetamol can relieve pain in
mild arthritis, but has no effect on the underlying inflammation,
redness, and swelling of the joint.
[24]
Regarding comparative
efficacy, studies show conflicting results when compared to NSAIDs. A
randomised controlled trial of chronic pain from osteoarthritis in adults found similar benefit from paracetamol and ibuprofen.
[25][26]
The efficacy of paracetamol when used in combination with weak opioids (such as
codeine) was assessed in data studies in 1996 and 2009,
[27][28]
which found improved efficacy for approximately 50% of patients but
increases in the number of patients experiencing adverse effects.
Combination drugs of paracetamol and strong opioids like morphine reduce
the amount of opioid needed and improve analgesic effect.
[29]
The American College of Rheumatology recommends paracetamol as one of
several treatment options for patients with arthritis pain of the hip,
hand, or knee that is refractory to non-pharmacological interventions
such as exercise and weight loss.
[30]
A joint statement of the German, Austrian, and Swiss headache
societies and the German Society of Neurology recommends the use of
paracetamol in combination with caffeine as one of several first line
therapies for treatment of tension or migraine headache.
[31]
In the treatment of acute migraine, it is superior to placebo, with 39%
of people experiencing pain relief at 1 hour compared to 20% in the
control group.
[32]
Based on a systematic review, paracetamol is recommended by the
American College of Physicians and the American Pain Society as a first
line treatment for low back pain.
[33][34] However a systematic review published by other authors concluded that evidence for its efficacy is lacking.
[35]
The combination of paracetamol with caffeine is superior to
paracetamol alone for the treatment of common pain conditions including
dental pain, postpartum pain, and headache.
[36]
Adverse effects
In recommended doses and for a limited course of treatment, the
side effects of paracetamol are mild to non-existent.
[37]
Liver damage
Acute
overdoses of paracetamol can cause potentially fatal
liver damage. According to the US
Food and Drug Administration, "Acetaminophen can cause serious liver damage if more than directed is used."
[38]
and in 2011 the FDA required manufacturers to update labels of all
prescription combination acetaminophen products to warn of the potential
risk for severe liver injury
[39] and launched a public education program to help consumers avoid overdose.
[40][41] The risk may be heightened by frequent consumption of alcohol.
Paracetamol toxicity is the foremost cause of
acute liver failure in the
Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia and New Zealand.
[42][43][44][45]
According to the FDA, in the United States there were "56,000 emergency
room visits, 26,000 hospitalizations, and 458 deaths per year related
to acetaminophen-associated overdoses during the 1990s. Within these
estimates, unintentional acetaminophen overdose accounted for nearly 25
percent of the emergency department visits, 10 percent of the
hospitalizations, and 25 percent of the deaths."
[46]
Paracetamol is metabolised by the liver and is
hepatotoxic; side effects are multiplied when combined with alcoholic drinks, and very likely in
chronic alcoholics or patients with liver damage.
[37][47] Some studies have suggested the possibility of a moderately increased risk of upper gastrointestinal complications such as
stomach bleeding when high doses are taken chronically.
[48] Kidney damage is seen in rare cases, most commonly in overdose.
[49] The
Food and Drug Administration
has warned doctors against prescribing paracetamol/narcotic
combinations whose dosages exceed 325 mg of paracetamol due to
hepatoxicity risks of greater magnitude than the therapeutic benefits
conferred.
[50]
Skin reactions
On August 2, 2013, the U.S.
Food and Drug Administration
(FDA) issued a new warning about paracetamol. It stated that the drug
could cause rare, and possibly fatal, skin reactions, such as
Stevens–Johnson syndrome and
toxic epidermal necrolysis.
Prescription-strength products will be required to carry a warning
label about skin reactions, and the FDA has urged manufacturers to do
the same with over-the-counter products.
[51]
Asthma
There is an association between paracetamol use and
asthma
but the weight of evidence of the collected studies strongly suggests
that the association reflects various forms of bias, the most prominent
of which is confounding by indication.
[52] The majority of the evidence does not support a causal role.
[53]
As of 2014, the
American Academy of Pediatrics and the
National Institute for Health and Care Excellence (NICE) continue to recommend paracetamol for pain and discomfort in children,
[54][55][56][57][58][59] but some experts have recommended that paracetamol use by children with asthma, or at risk for asthma, should be avoided.
[60][61]
Other factors
In contrast to aspirin, paracetamol does not prevent blood from clotting (it is not an
antithrombotic), and thus may be used in patients where failure of blood
coagulation is a concern; and it does not cause gastric irritation.
[62] However, paracetamol does not help reduce inflammation, while aspirin does.
[63] Compared to
ibuprofen—whose side effects may include diarrhea, vomiting and abdominal pain—paracetamol has fewer adverse gastrointestinal effects.
[64]
Unlike aspirin, paracetamol is generally considered safe for children, as it is not associated with a risk of
Reye's syndrome in children with viral illnesses.
[65]
Paracetamol when taken recreationally with opioids may cause hearing loss.
[66][better source needed]
Overdose
Untreated paracetamol overdose results in a lengthy, painful illness.
Signs and symptoms of paracetamol toxicity may initially be absent or
non-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, with
nausea,
vomiting, sweating, and
pain as
acute liver failure starts.
[67]
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.
[68] The process of dying from an overdose usually takes three to five days.
Paracetamol hepatotoxicity is, by far, the most common cause of acute
liver failure in both the United States and the United Kingdom.
[45][69] Paracetamol overdose results in more calls to
poison control centers in the US than overdose of any other pharmacological substance.
[70] Toxicity of paracetamol is believed to be due to its
quinone metabolite.
[71]
Untreated overdose can lead to
liver failure and death within days. Treatment is aimed at removing the paracetamol from the body and replacing
glutathione.
[71] Activated charcoal
can be used to decrease absorption of paracetamol if the patient
presents for treatment soon after the overdose. While the antidote,
acetylcysteine,
(also called N-acetylcysteine or NAC) acts as a precursor for
glutathione, helping the body regenerate enough to prevent or at least
decrease the possible damage to the liver, a
liver transplant is often required if damage to the liver becomes severe.
[42][72] NAC was usually given following a treatment
nomogram
(one for patients with risk factors, and one for those without) but the
use of the nomogram is no longer recommended as evidence to support the
use of risk factors was poor and inconsistent, and many of the risk
factors are imprecise and difficult to determine with sufficient
certainty in clinical practice.
[73] NAC also helps in neutralizing the imidoquinone metabolite of paracetamol.
[71] Renal failure is also a possible side effect.
There were tablets available until 2004 (brand-name in the UK Paradote) that combined paracetamol with an antidote (
methionine),
to protect the liver in case of an overdose. One theoretical, but
rarely if ever used, option in the United States is to request a
compounding pharmacy to make a similar drug mix for at-risk patients.
In June 2009, a
U.S. Food and Drug Administration
(FDA) advisory committee recommended that new restrictions should be
placed on paracetamol usage in the United States to help protect people
from the potential toxic effects. The maximum dosage at any given time
would be decreased from 1000 mg to 650 mg, while combinations of
paracetamol and
narcotic analgesics
would be prohibited. Committee members were particularly concerned by
the fact that the present maximum dosages of paracetamol had been shown
to produce alterations in
hepatic function.
[74]
In January 2011, the FDA asked manufacturers of prescription
combination products containing paracetamol to limit the amount of
paracetamol to no more than 325 mg per tablet or capsule and began
requiring manufacturers to update the labels of all prescription
combination paracetamol products to warn of the potential risk of severe
liver damage.
[75][76][77][78] Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.
[76][78] In November 2011, the
Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.
[79]
Pregnancy
Experimental studies in animals and cohort studies in humans indicate
no detectable increase in congenital malformations associated with
paracetamol use during
pregnancy.
[80] Additionally, paracetamol does not affect the closure of the fetal ductus arteriosus as NSAIDs can.
[81] However, paracetamol use by mother during pregnancy is associated with an increased risk of childhood
asthma.
[82]
Chemical properties
Paracetamol consists of a
benzene ring core,
substituted by one
hydroxyl group and the
nitrogen atom of an
amide group in the
para (1,4)
pattern.
[83] The amide group is
acetamide (ethanamide). It is an extensively
conjugated system, as the
lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the
p orbital on the
carbonyl
carbon, and the lone pair on the carbonyl oxygen are all conjugated.
The presence of two activating groups also make the benzene ring highly
reactive toward
electrophilic aromatic substitution. As the substituents are
ortho, para-directing and
para
with respect to each other, all positions on the ring are more or less
equally activated. The conjugation also greatly reduces the
basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the
phenoxide anion.
Mechanism of action
To date, the mechanism of action of paracetamol is not completely understood. The main mechanism proposed is the inhibition of
cyclooxygenase (COX), and recent findings suggest that it is highly selective for
COX-2.
[84] Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting
thromboxanes.
[84] While it has
analgesic and
antipyretic properties comparable to those of
aspirin or other
NSAIDs, its peripheral anti-inflammatory activity is usually limited by several factors, one of which is the high level of
peroxides present in
inflammatory lesions. However, in some circumstances, even peripheral anti-inflammatory activity comparable to
NSAIDs can be observed.
An article
[85]
in Nature Communications from researchers in London, UK and Lund,
Sweden in November 2011 has found a hint to the analgesic mechanism of
paracetamol, being that the metabolites of paracetamol e.g.
NAPQI, act on
TRPA1-receptors in the spinal cord to suppress the signal transduction from the superficial layers of the dorsal horn, to alleviate pain.
This conclusion has been contested in a new hypothesis paper
[86] on how paracetamol might act. The author concedes that
NAPQI
is the active metabolite but that this reactive compound should react
not only with the thiol in TRPA1 but also with any other suitably
available nucleophile that it happens to encounter. It is suggested that
thiol groups in cysteine proteases, e.g. the proteases that take part
in the processing of procytokines, such as those generating
IL-1β and
IL-6, might be the targets giving rise to overall analgesic effects.
The COX family of enzymes are responsible for the metabolism of
arachidonic acid to
prostaglandin H2,
an unstable molecule that is, in turn, converted to numerous other
pro-inflammatory compounds. Classical anti-inflammatories such as the
NSAIDs block this step. Only when appropriately oxidised is the COX enzyme highly active.
[87][88] Paracetamol reduces the oxidised form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.
[89][90] This leads to a reduced amount of
prostaglandin E2 in the CNS, thus lowering the hypothalamic set-point in the thermoregulatory centre.
Aspirin is known to inhibit the
cyclooxygenase (COX) family of enzymes and, because paracetamol's action is partially similar to aspirin's,
[clarification needed]
much research has focused on whether paracetamol also inhibits COX. It
is now clear that paracetamol acts via at least two pathways.
[89][91][92][93]
The exact mechanisms by which COX is inhibited in various
circumstances are still a subject of discussion. Because of differences
in the activity of paracetamol, aspirin, and other NSAIDs, it has been
postulated that further COX variants may exist. One theory holds that
paracetamol works by inhibiting the
COX-3 isoform—a COX-1
splice variant—of the COX family of enzymes.
[84]
When expressed in dogs, this enzyme shares a strong similarity to the
other COX enzymes, produces pro-inflammatory chemicals, and is
selectively inhibited by paracetamol.
[94]
However, some research has suggested that, in humans and mice, the
COX-3 enzyme is without inflammatory action and paracetamol's blockage
of it is not significant in its functioning in humans.
[84][92]
Another possibility is that paracetamol blocks cyclooxygenase (as in
aspirin), but that, in an inflammatory environment where the
concentration of peroxides is high, the high oxidation state of
paracetamol prevents its actions. This idea would mean that paracetamol
has no direct effect at the site of inflammation, but instead acts in
the CNS where the environment is not oxidative, to reduce temperature,
etc.
[94]
Paracetamol also modulates the
endogenous cannabinoid system.
[95] Paracetamol is metabolised to
AM404,
a compound with several actions; what is most important is that it
inhibits the reuptake of the endogenous cannabinoid/vanilloid
anandamide
by neurons. Anandamide reuptake lowers synaptic levels of anandamide
and results in more activation of the main pain receptor (nociceptor) of
the body, the
TRPV1
(older name: vanilloid receptor). By inhibiting anandamide reuptake,
levels in the synapse remain high and are able to desensitise the TRPV1
receptor much like
capsaicin. Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine.
[96]
Both of these actions by themselves have been shown to reduce pain, and
are a possible mechanism for paracetamol. However, it has been
demonstrated that, when cannabinoid receptors are blocked with synthetic
antagonists, paracetamol's analgesic effects are prevented, suggesting
its pain-relieving action involves the endogenous cannabinoid system.
[97] Spinal
TRPA1 receptors have also been demonstrated to mediate antinociceptive effects of paracetamol and Δ9-tetrahydrocannabinol in mice.
[98]
Increase of social behavior in mice dosed with paracetamol (which corresponds to a reduction of
social rejection response in humans) does not appear to be due to
cannabinoid receptor type 1 activity. It may result from
serotonin receptor agonism.
[99]
Pharmacokinetics
Main pathways of paracetamol metabolism
(click to enlarge). Pathways shown in blue and purple lead to non-toxic metabolites; the pathway in red leads to toxic
NAPQI.
After oral administration it is rapidly absorbed by the GI tract; its volume of distribution is roughly 50 L.
[14]
Paracetamol is
metabolised primarily in the
liver, into toxic and non-toxic products. Three
metabolic pathways are notable:
[71]
- Glucuronidation (45-55%)[3]
- Sulfation (sulfate conjugation) accounts for 20–30%.[3]
- N-hydroxylation and dehydration, then GSH conjugation, accounts for less than 15%. The hepatic cytochrome P450 enzyme system metabolises paracetamol, forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzoquinone imine)(also known as N-acetylimidoquinone).[71][100] NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.[100]
All three pathways yield final products that are inactive, non-toxic,
and eventually excreted by the kidneys. In the third pathway, however,
the intermediate product NAPQI is toxic. NAPQI is primarily responsible
for the
toxic effects of paracetamol; this constitutes an example of
toxication.
[101] Production of NAPQI is due primarily to two
isoenzymes of cytochrome P450:
CYP2E1 and
CYP3A4.
[101] At usual doses, NAPQI is quickly detoxified by conjugation with glutathione.
[71][100]
Synthesis
In a small-scale laboratory, paracetamol is prepared by a three-reaction sequence. First,
nitration of
phenol with
sodium nitrate gives a mixture of two isomers, from which the wanted
4-nitrophenol (bp ~93 °C) can easily be separated by
steam distillation. In this
electrophilic aromatic substitution
reaction, phenol's oxygen is strongly activating, thus the reaction
requires only mild conditions as compared to nitration of benzene
itself. The
nitro group is then reduced to an amine, giving
4-aminophenol. This reaction can be accomplished using
sodium borohydride. Finally, the amine is acetylated with
acetic anhydride.
[102] The industrial process is analogous, but hydrogenation is used instead of the sodium borohydride reduction.
[103][104]
An alternative industrial synthesis developed by
Hoechst–
Celanese involves direct acylation of phenol with acetic anhydride catalyzed by HF, conversion of the ketone to a
ketoxime with
hydroxylamine, followed by the acid-catalyzed
Beckmann rearrangement to give the amide.
[104][105]
Demand for paracetamol in the United States was estimated at 30–35
thousand tonnes per year in 1997, equal to the demand from the rest of
the world.
[106]
Reactions
4-Aminophenol may be obtained by the amide
hydrolysis of paracetamol.
4-Aminophenol prepared this way, and related to the commercially available
Metol, has been used as a developer in photography by hobbyists.
[107] 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.
[108]
History
Julius Axelrod (pictured) and
Bernard Brodie demonstrated that acetanilide and phenacetin are both metabolised to paracetamol, which is a better tolerated analgesic.
Acetanilide was the first
aniline
derivative serendipitously found to possess analgesic as well as
antipyretic properties, and was quickly introduced into medical practice
under the name of
Antifebrin by A. Cahn and P. Hepp in 1886.
[109] But its unacceptable toxic effects, the most alarming being
cyanosis due to
methemoglobinemia, prompted the search for less toxic aniline derivatives.
[91] Harmon Northrop Morse had already synthesised paracetamol at
Johns Hopkins University via the reduction of
p-nitrophenol with
tin in glacial
acetic acid in 1877,
[110][111] but it was not until 1887 that clinical pharmacologist
Joseph von Mering tried paracetamol on patients.
[91] In 1893, von Mering published a paper reporting on the clinical results of paracetamol with
phenacetin, another aniline derivative.
[112]
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.
[113] Overshadowed in part by
aspirin, introduced into medicine by
Heinrich Dreser
in 1899, phenacetin was popular for many decades, particularly in
widely advertised over-the-counter "headache mixtures", usually
containing phenacetin, an
aminopyrine derivative of aspirin, caffeine, and sometimes a
barbiturate.
[91]
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 paracetamol.
[113] In 1947
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.
[114] In three papers published in the September 1948 issue of the
Journal of Pharmacology and Experimental Therapeutics,
Bernard Brodie,
Julius Axelrod
and Frederick Flinn confirmed using more specific methods that
paracetamol was the major metabolite of acetanilide in human blood, and
established that it was just as efficacious an analgesic as its
precursor.
[115][116][117] 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 metabolised to paracetamol.
[118] This led to a "rediscovery" of paracetamol.
[91] It has been suggested that contamination of paracetamol with
4-aminophenol, the substance von Mering synthesised it from, may be the cause for his spurious findings.
[113]
Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol,
aspirin, and
caffeine.
[111] 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.
[111] Paracetamol was marketed in 1953 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.
[111][113][119] In 1955, paracetamol was marketed as Children's
Tylenol Elixir by
McNeil Laboratories.
[120] In 1956, 500
mg
tablets of paracetamol went on sale in the United Kingdom under the
trade name Panadol, produced by Frederick Stearns & Co, a subsidiary
of
Sterling Drug
Inc. Panadol was originally available only by prescription, for the
relief of pain and fever, and was advertised as being "gentle to the
stomach," since other analgesic agents of the time contained aspirin, a
known stomach irritant. 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.
[111]
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.
[91]
The U.S.
patent on paracetamol has long expired, and generic versions of the drug are widely available under the
Drug Price Competition and Patent Term Restoration Act
of 1984, although certain Tylenol preparations were protected until
2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for
"Extended release acetaminophen particles".
[121]
Society and culture
Available forms
For comparison: The pure drug is a white crystalline powder.
Paracetamol is available in a
tablet,
capsule, liquid suspension,
suppository,
intravenous,
intramuscular and
Effervescent
form. The common adult dose is 500 mg to 1000 mg. The recommended
maximum daily dose, for adults, is 4000 mg. In recommended doses,
paracetamol is generally safe for children and infants, as well as for
adults,
[122] although rare cases of acute liver injury have been linked to amounts lower than 2500 mg per day.
[123]
In some formulations, paracetamol is combined with the
opioid codeine, sometimes referred to as
co-codamol (
BAN).
In the U.S., this combination is available only by prescription, while
the lowest-strength preparation is over-the-counter in Canada, and, in
other countries, other strengths may be available over the counter.
[citation needed] Paracetamol is also combined with other opioids such as
dihydrocodeine, referred to as
co-dydramol (
BAN),
oxycodone or
hydrocodone. Another very commonly used analgesic combination includes paracetamol in combination with
propoxyphene napsylate. A combination of paracetamol, codeine, and the calmative
doxylamine succinate is also available. The efficacy of paracetamol/codeine combinations have been questioned by recent research.
[29]
Paracetamol is commonly used in multi-ingredient preparations for
migraine headache, typically including
butalbital and paracetamol with or without
caffeine, and sometimes containing codeine.
Paracetamol is sometimes combined with
phenylephrine hydrochloride.
[124] Sometimes a third active ingredient, such as
ascorbic acid,
[124][125] caffeine,
[126][127] chlorpheniramine maleate,
[128] or
guaifenesin.
[129][130][131] is added to this combination.
Veterinary use
Cats
Paracetamol is extremely toxic to cats, which lack the necessary
glucuronyl transferase enzymes to safely break it down. Initial symptoms include vomiting, salivation, and discolouration 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 (
methemoglobemia and
hemolytic anemia).
[132]
Treatment with
N-acetylcysteine,
[133] methylene blue or both is sometimes effective after the ingestion of small doses of paracetamol.
Dogs
Although paracetamol is believed to have no significant
anti-inflammatory activity, it has been reported as effective as aspirin
in the treatment of musculoskeletal pain in dogs.
[134]
A paracetamol-codeine product (trade name Pardale-V)
[135] licensed for use in dogs is available on veterinary prescription in the UK.
[135] It should be administered to dogs only on veterinary advice and with extreme caution.
[135]
The main effect of toxicity in dogs is liver damage, GI ulceration has been reported.
[133][136][137][138] N-acetylcysteine treatment is efficacious in dogs when administered within a 2 hours of paracetamol ingestion.
[133][134]
Snakes
Paracetamol is also lethal to snakes, and has been suggested as a chemical control program for the invasive
brown tree snake (
Boiga irregularis) in
Guam.
[139][140] Doses of 80 mg are inserted into dead mice scattered by helicopter.
[141]
Controversy
In September 2013 an episode of
This American Life entitled "Use Only as Directed"
[142] highlighted deaths from acetaminophen overdose. This report was followed by two reports by
ProPublica[143][144]
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.".
A report prepared by an internal FDA working group describes a
history of FDA initiatives designed to educate consumers about the risk
of acetaminophen overdose, and notes that one challenge to the Agency
has been "identifying the appropriate message about the relative safety
of acetaminophen, especially compared to other OTC pain relievers (e.g.,
aspirin and other NSAIDs)". The report notes that "Chronic use of
NSAIDs is also associated with significant morbidity and mortality.
NSAID gastrointestinal risk is substantial, with deaths and
hospitalization estimated in one publication as 3200 and 32,000 per year
respectively. Possible cardiovascular toxicity with chronic NSAID use
has been a major discussion recently", finally noting that "The goal of
the educational efforts is not to decrease appropriate acetaminophen use
or encourage substitution of NSAID use, but rather to educate consumers
so that they can avoid unnecessary health risks."
[13]
Classification
Paracetamol is part of the class of drugs known as "
aniline analgesics"; it is the only such drug still in use today.
[91] It is not considered an NSAID because it does not exhibit significant anti-inflammatory activity (it is a weak COX inhibitor).
[145][146] This is despite the evidence that paracetamol and NSAIDs have some similar pharmacological activity.
[147
