Paracetamol or
acetaminophen
chemically named N-acetyl-p-aminophenol, is a widely used
over-the-counter analgesic (pain reliever) and
antipyretic (fever reducer).
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.Though paracetamol is used to treat inflammatory pain, it is not generally classified as an
NSAID because it exhibits only weak anti-inflammatory activity.
The onset of analgesia is approximately 11–29.5 minutes after
oral administration of paracetamol and its
half-life is 1–4 hours. While generally safe for use at recommended doses (
1,000 mg per single dose and up to
4,000 mg per day for adults)
acute
overdoses of paracetamol can cause potentially fatal
liver damage. The risk may be heightened by chronic
alcohol abuse; ethanol increases the number of CYP2E1 enzymes, a cytochrome P450 enzyme that leads to toxic byproducts of acetaminophen.
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.
It is the active metabolite
phenacetin,
once popular as an analgesic and antipyretic in its own right. However,
unlike phenacetin and its combinations, paracetamol is not considered
carcinogenic at therapeutic doses.The words
acetaminophen (used in the United States,
Canada, Japan, South Korea, Hong Kong, and Iran) and
paracetamol (used elsewhere) both come from a chemical name for the compound:
para-
acetyl
aminophenol and
para-
acetyl
aminophen
ol. In some contexts, it is simply abbreviated as
APAP, for
acetyl-
para-
amino
phenol.
Medical uses
Fever
Paracetamol is approved for reducing
fever in people of all ages.
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). The efficacy of paracetamol by itself in children with fevers has been questioned and a meta-analysis showed that it is less effective than
ibuprofen.
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, it has in recent
[] years increasingly become a common household drug.
Paracetamol can relieve pain in mild arthritis
[citation needed] but has no effect on the underlying inflammation, redness, and swelling of the joint. It is as effective as the non-steroidal
anti-inflammatory drug (
NSAID)
ibuprofen in relieving the pain of
osteoarthritis of the knee.
[citation needed]
Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as the
NSAIDs
aspirin and ibuprofen. But research studies analysis showed that
ibuprofen and paracetamol have similar effects in the treatment of
headache.
Regarding comparative
efficacy, studies show conflicting results when compared to NSAIDs. A
randomized controlled trial of chronic pain from osteoarthritis in adults found similar benefit from paracetamol and ibuprofen.
[18][19]
The efficacy of paracetamol when used in a combination form with weak opioids (such as codeine) has been questioned by recent
[when?]
data studies; the small amount of data available have made reaching a
conclusion difficult. Combination drugs of paracetamol and strong
opioids like morphine have been shown
[by whom?]
to reduce the amount of opioid used and improve analgesic effect as
well as discouraging overuse of addictive opioids due to APAP's toxic
effects, as it depletes glutathione and thus exacerbates disease in
general.
A randomized controlled trial of acute musculoskeletal pain in
children found that the standard over-the-counter dose of ibuprofen
gives greater pain relief than the standard dose of paracetamo
l
Psychological effects
Paracetamol acts on, and suppresses pain through, the
central nervous system rather than the
peripheral nervous system. Recent research suggests that it deadens the neural response that causes the pain of
social rejection as well as neural responses related to physical pain
Adverse effects
Paracetamol is metabolized 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.Prolonged daily use increases the risk of upper gastrointestinal complications such as
stomach bleeding and may cause kidney or liver damage. And chronic users of paracetamol may have a higher risk of developing
blood cancer. However in recommended doses and for a limited course of treatment, the
side effects of paracetamol are mild to non-existent
In contrast to aspirin, paracetamol is not an
antithrombotic, and thus may be used in patients where
coagulation is a concern, and it does not cause gastric irritation.However, paracetamol does not help reduce inflammation, while aspirin does.Compared to
ibuprofen—whose side effects may include diarrhea, vomiting and abdominal pain—paracetamol has fewer adverse gastrointestinal effects.
Until 2010, paracetamol was believed safe in pregnancy (as it does not affect the closure of the fetal
ductus arteriosus as NSAIDs can). However, in a study published in October 2010 it has been linked to
infertility in the subsequent adult life of the fetusUnlike aspirin, it is safe for children, as paracetamol is not associated with a risk of
Reye's syndrome in children with viral illnesses.
In one study, paracetamol use for fever in the first year of life was associated with a moderate increase in the incidence of
asthmatic
symptoms at 6–7 years, and that paracetamol use, both in the first year
of life and in children aged 6–7 years, was associated with a moderate
increased incidence of
rhinoconjunctivitis and
eczema.
On August 2, 2013, the
FDA issued a new warning about Acetominophen, like
Tylenol.
It stated that the drug could cause rare, and possibly fatal, skin
reactions. Prescription-strength products will be required to carry a
warning label about skin reactions, and the FDA is urging manufacturers
to do the same with over the counter Acetominophen pills. The FDA says
the there is a risk of potentially serious skin reactions, such as
Stevens-Johnson Syndrome and
Toxic Epidermal Necrolysis.
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.
People who take overdoses of paracetamol do not lose consciousness,
although most people who use paracetamol wrongly believe that they will
be rendered unconscious by the drug.
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.Toxicity of paracetamol arises often due to its quinone metabolite Paracetamol overdose results in more calls to
poison control centers in the US than overdose of any other pharmacological substance.
Untreated overdose can lead to
liver failure and death within days. 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. While the antidote,
acetylcysteine,
(also called N-acetylcysteine or NAC) acts as a precursor for
glutathione, helping the body regenerate enough to prevent damage to the
liver, a
liver transplant is often required if damage to the liver becomes severe.
N-Acetylcysteine also helps in neutralizing the imidoquinone metabolite of acetaminophen.
Renal failure is also a possible side effect.
There were tablets available until 2004 (brand-name in the UK Paradote) that combine 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 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.
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 for
severe liver damage.
[43][44][45][46]
Manufacturers will have three years to limit the amount of paracetamol
in their prescription drug products to 325 mg per dosage unit.
[] In November 2011, the
Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.
Classification
Paracetamol is part of the class of drugs known as "
aniline analgesics"; it is the only such drug still in use today.
[48] It is not considered an NSAID because it does not exhibit significant anti-inflammatory activity (it is a weak COX inhibitor).
[49][50] This is despite the evidence that paracetamol and NSAIDs have some similar pharmacological activity.
[51]
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.
[52] 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
[53]
in Nature Communications from researchers in London, UK and Lund,
Sweden in November 2011 has found a hint to the analgesic mechanism of
paracetamol (acetaminophen), 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
[54] 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.
Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting
thromboxanes.
[52]
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 oxidized is the COX enzyme highly active.
[55][56]
Paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.
[57][58] This leads to a reduced amount of
prostaglandin E2 in the CNS, thus lowering the hypothalamic set-point in the thermoregulatory centre.
Paracetamol also modulates the
endogenous cannabinoid system.
[59] Paracetamol is metabolized 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 would result in lower synaptic levels
and less 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 desensitize the TRPV1
receptor much like
capsaicin. Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine.
[60]
Either of these actions by themselves has been shown to reduce pain,
and are a possible mechanism for paracetamol. However, it has been
demonstrated that, after blocking cannabinoid receptors with synthetic
antagonists, paracetamol's analgesic effects are prevented, suggesting
its pain-relieving action involves the endogenous cannabinoid system.
[61] Spinal
TRPA1 receptors have also been demonstrated to mediate antinociceptive effects of paracetamol and Δ9-tetrahydrocannabinol in mice.
[62]
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.
[48][57][63][64]
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.
[52]
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.
[65]
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.
[52][63]
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.
[65] The exact mechanism by which paracetamol is believed to affect COX-3 is disputed.
Paracetamol's increase of social behavior in mice (which corresponds to its 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.
[66]
Structure and reactivity
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.
[67] 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.
Synthesis
In the laboratory, paracetamol is prepared by
nitrating phenol with
sodium nitrate; steam-distillation of the result to collect the
4-nitrophenol (bp ~93°C) from the other isomers; and reducing the
nitro group with
sodium borohydride. The resultant
4-aminophenol is then acetylated with
acetic anhydride.
[68] In this reaction,
phenol
is strongly activating, thus the reaction requires only mild conditions
(cf. the nitration of benzene). The industrial process is analogous,
but hydrogenation is used instead of the sodium borohydride reduction.
[69][70]
A simpler synthesis 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.
[70][71]
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.
[72]
Metabolism
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.
Paracetamol is
metabolised primarily in the
liver, into toxic and non-toxic products. Three
metabolic pathways are notable:
[40]
- Glucuronidation is believed to account for 40% to two-thirds of the metabolism of paracetamol.[73]
- Sulfation (sulfate conjugation) may account for 20–40%.[73]
- N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. The hepatic cytochrome P450 enzyme system metabolizes paracetamol, forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzo-quinone imine)(also known as N-acetylimidoquinone).[40][74] NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.[74]
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.
Production of NAPQI is due primarily to two
isoenzymes of cytochrome P450:
CYP2E1 and
CYP1A2. The P450 gene is highly
polymorphic, however, and individual differences in paracetamol toxicity are believed due to a third isoenzyme,
CYP2D6. Genetic polymorphisms in
CYP2D6 may contribute to significantly different rates of production of NAPQI. Furthermore, individuals can be classified as
"extensive", "ultrarapid", "intermediate" and "poor" metabolizers
(producers of NAPQI), depending on their levels of CYP2D6 expression.
Although CYP2D6 metabolises paracetamol into NAPQI to a lesser extent
than other P450 enzymes, its activity may contribute to paracetamol
toxicity in extensive and ultrarapid metabolisers, and when paracetamol
is taken at very large doses.
[75] At usual doses, NAPQI is quickly detoxified by conjugation with glutathione.
[40][74]
Following overdose, and possibly also in extensive and ultrarapid
metabolizers, this detoxification pathway becomes saturated, and, as a
consequence, NAPQI accumulates causing liver and renal toxicity.
[40]
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.
[76] 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.
[77]
History
Julius Axelrod (pictured) and
Bernard Brodie demonstrated that acetanilide and phenacetin are both metabolized 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.
[78] But its unacceptable toxic effects, the most alarming being
cyanosis due to
methemoglobinemia, prompted the search for less toxic aniline derivatives.
[48] Harmon Northrop Morse had already synthesized paracetamol at
Johns Hopkins University via the reduction of
p-nitrophenol with
tin in glacial
acetic acid in 1877,
[79][80] but it was not until 1887 that clinical pharmacologist
Joseph von Mering tried paracetamol on patients.
[48] In 1893, von Mering published a paper reporting on the clinical results of paracetamol with
phenacetin, another aniline derivative.
[81]
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.
[82] 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.
[48]
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.
[82] 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.
[83] 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.
[84][85][86] 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.
[87] This led to a "rediscovery" of paracetamol.
[48] It has been suggested that contamination of paracetamol with
4-aminophenol, the substance von Mering synthesized it from, may be the cause for his spurious findings.
[82]
Paracetamol was first marketed in the United States in 1953 by
Sterling-Winthrop Co., which promoted it as preferable to aspirin since it was safe to take for children and people with ulcers.
[82] The best known brand today for paracetamol in the United States,
Tylenol, was established in 1955 when
McNeil Laboratories
started selling paracetamol as a pain and fever reliever for children,
under the brand name Tylenol Children's Elixir—the word "tylenol" was a
contraction of
para-ace
tylaminoph
enol.
[88] 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.
[80]
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.
[48]
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".
[89]
Available forms
Paracetamol is available in a
tablet,
capsule, liquid suspension,
suppository,
intravenous, and
intramuscular
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,
[90] although rare cases of acute liver injury have been linked to amounts lower than 2500 mg per day.
[91]
Panadol, which is marketed in Africa, Asia, Europe, Central America, and
Australasia,
is the most widely available brand of paracetamol, sold in over 80
countries. In North America, paracetamol is sold in generic form
(usually labeled as acetaminophen) or under a number of trade names, for
instance,
Tylenol (
McNeil-PPC, Inc.),
Anacin-3,
Tempra, Datril, and Ofirmev. While there is brand named paracetamol
available in the UK (e.g. Panadol), unbranded or generic paracetamol is
more commonly sold.
Acamol, a brand name for paracetamol produced by
Teva Pharmaceutical Industries in
Israel,
is one of the most widely used drugs in that country. In the
Philippines, the largest-selling paracetamol brand is Biogesic,
manufactured by the drug giant United Laboratories. Biogesic tablet
sales reach nearly a billion units each year in the country alone, not
including liquid suspension formats. The brand is also available in most
of the
ASEAN
countries where the drug giant has market presence. In Europe, the most
common brands of paracetamol are Efferalgan and Doliprane. In India,
the most common brand of paracetamol is Crocin manufactured by Glaxo
SmithKline Asia. In Bangladesh the most popular two brand are Napa and
Renova manufactured by Beximco Pharma and Opsonin Pharma respectively.
In China paracetamol is sold over the counter as
Duìyǐxiān'ānjīfēn Piàn (对乙酰氨基酚片).
[92] Likewise in Japan it is sold under the name Acetaminophen (アセトアミノフェン
Asetoaminofen). In North Korea the DPRK-Swiss joint venture
PyongSu Pharma markets the drug as PyongSu Cetamol.
In some formulations, paracetamol is combined with the
opioid codeine, sometimes referred to as
co-codamol (
BAN).
In the United States and Canada, this is marketed under the name of
Tylenol #1/2/3/4, which contain 8–10 mg, 15 mg, 30 mg, and 60 mg of
codeine,
respectively. 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. There are generic forms of these combinations as well.
In the UK and in many other countries, this combination is marketed
under the names of
Tylex
CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum,
Hedex, Mexalen, Nofedol, Panocod, Paralen, Pediapirin, Perfalgan, and
Solpadeine. Paracetamol is also combined with other opioids such as
dihydrocodeine, referred to as
co-dydramol (
BAN),
oxycodone or
hydrocodone, marketed in the U.S. as
Percocet and
Vicodin, respectively. Another very commonly used analgesic combination includes paracetamol in combination with
propoxyphene napsylate, sold under the brand name
Darvocet. A combination of paracetamol, codeine, and the calmative
doxylamine succinate is marketed as Syndol or Mersyndol. The efficacy of paracetamol/codeine combinations have been questioned by recent research.
[20]
Paracetamol is commonly used in multi-ingredient preparations for
migraine headache, typically including
butalbital and paracetamol with or without
caffeine, and sometimes containing codeine.
Veterinary use
Paracetamol is extremely toxic to cats,
[93] which lack the necessary
glucuronyl transferase enzymes to safely break it down.
[93]
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).
[94] Treatment with
N-acetylcysteine,
[93] methylene blue or both is sometimes effective after the ingestion of small doses of paracetamol.
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.
[95] A paracetamol-codeine product (trade name Pardale-V)
[96] licensed for use in dogs is available on veterinary prescription in the UK.
[96] It should be administered to dogs only on veterinary advice and with extreme caution.
[96] The main effect of toxicity in dogs is liver damage, GI ulceration has been reported.
[93][97][98][99] N-acetylcysteine treatment is efficacious in dogs when administered within a 2 hours of paracetamol ingestion.
[93][95]
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.
[100][101] Doses of 80 mg are inserted into dead mice scattered by helicopter.
[102]
Disto-Angular. The long axis of the 3rd molar is angled distally / posteriorly 
Horizontal. The long axis of the 3rd molar is horizontal. 
