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Review Article
Acetaminophen: Old Drug, New Issues
Anita Aminoshariae, DDS, MS,* and Asma Khan, BDS, PhD†
Abstract
Introduction: The purpose of this review was to discuss
new issues related to safety, labeling, dosing, and a better understanding of the analgesic effect of acetaminophen. Methods: The MEDLINE, Embase, Cochrane, and
PubMed databases were searched. Additionally, the
bibliography of all relevant articles and textbooks
were manually searched. Two reviewers independently
selected the relevant articles. Results: Concerns about
acetaminophen overdose and related liver failure have
led the US Food and Drug Administration to mandate
new labeling on acetaminophen packaging. In addition,
large-scale epidemiologic studies increasingly report evidence for second-generation adverse effects of acetaminophen. Prenatal exposure to acetaminophen is
associated with neurodevelopmental and behavioral
disorders. Recent studies also suggest that acetaminophen is a hormone disrupter (ie, it interferes with sex
and thyroid hormone function essential for normal brain
development) and thus may not be considered a safe
drug during pregnancy. Finally, emerging evidence suggests that although the predominant mechanism by
which acetaminophen exerts its therapeutic effect is
by inhibition of cyclooxygenase, multiple other mechanisms also contribute to its analgesic effect. Conclusions: Available evidence suggests that indiscriminate
usage of this drug is not warranted. and its administration to a pregnant patient should be considered with
great caution. (J Endod 2015;41:588–593)
Key Words
Acetaminophen, mechanism of action, paracetamol, review, side effects
From the *Department of Endodontics, Case School of
Dental Medicine, Cleveland, Ohio; and †Department of Endodontics, University of North Carolina, Chapel Hill, North Carolina.
Address requests for reprints to Dr Anita Aminoshariae,
2123 Abington Road A 280, Cleveland, OH 44106. E-mail
address: [email protected]
0099-2399/$ - see front matter
Copyright ª 2015 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2015.01.024
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Aminoshariae and Khan
A
cetaminophen (also known as N-acetyl-p-aminophenol or APAP) or paracetamol
(PARA) is 1 of the most popular analgesic and antipyretic agents in the United States
(1). Because PARA is not widely recognized in the United States, in this article acetaminophen will be used. Acetaminophen is a member of the aniline family of analgesics, and
it is the only such drug available in the United States.
A January 13, 2011, Food and Drug Administration (FDA) Drug Safety Communication states that ‘‘acetaminophen-containing prescription products are safe and effective when used as directed, though all medications carry some risks’’ (2). Indeed,
during the past decade, acetaminophen has been identified as the leading cause of acute
liver failure in the United States, and up to 50% of the cases are caused by an unintentional overdose (3–6). To address the issues surrounding acetaminophen toxicity, the
FDA Center for Drug Evaluation and Research prepared an internal report that formed
the basis for discussion at the 2009 advisory committee meeting to mandate new
labeling on over-the-counter acetaminophen packaging (7). Subsequently, on January
13, 2011, confirming acetaminophen as a dose-dependent hepatotoxin, the FDA asked
drug manufactures to limit the strength of acetaminophen in prescription drug products
(eg, acetaminophen-opioid combinations) to 325 mg per tablet, capsule, or other
dosage unit (2). On January 14, 2014, the FDA called on health care professionals
to discontinue prescribing and dispensing prescription combination drug products
with more than 325 mg acetaminophen (8). Ultimately, on March 26, 2014, the FDA
and the pharmaceutical industry took action to protect consumers from the risk of severe liver damage by formally withdrawing from the market all prescription combination drug products with more than 325 mg acetaminophen (9). The FDA Center for
Drug Evaluation and Research recommendation to limit the dose (10) was an intervention designed to reduce the potential of an overdose occurring if a patient was not using
acetaminophen properly or if, unknowingly, a patient was using multiple
acetaminophen-containing products (11). In anticipation, McNEIL-PPC, Inc (Fort
Washington, PA), the producer of the Tylenol brand of acetaminophen, has already lowered the maximum recommended daily dose for single-ingredient Extra Strength TYLENOL from 4000 mg/d to 3000 mg/d (12, 13). Recent evidence also suggests that
acetaminophen has significant adverse effects when taken at recommended doses
during pregnancy. If this reflects causality, the safety of acetaminophen during
pregnancy must be questioned.
Finally, it is becoming increasingly clear that acetaminophen-induced antinociception is derived from synergism between peripheral, spinal, and supraspinal sites (14,
15). A clearer understanding of these mechanisms holds the key to reducing
acetaminophen-related adverse effects while optimizing analgesia. The purpose of
this article was to discuss new issues related to safety, labeling, dosing, and a better understanding of the antinociceptive action of acetaminophen.
Pharmacology of Acetaminophen
Mechanisms of Action
For many decades, the mechanism of action of acetaminophen was unclear. It is
now known that acetaminophen blocks prostaglandin synthesis from arachidonic acid
by inhibiting the enzymes cyclooxygenase (COX)-1 and -2. There are 2 sources of arachidonic acid. In most tissues, cytosolic phospholipase A2 hydrolyzes phospholipids to
yield arachidonic acid. In the brain, liver, and lung, monoacylglycerol lipase hydrolyzes
the endocannabinoid 2-arachidonoylglycerol to liberate arachidonic acid (16). Therapeutic concentrations of acetaminophen inhibit COX activity when the levels of arachidonic acid and peroxide are low but have little effect when the levels of arachidonic acid
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or peroxide are high as seen in severe inflammatory conditions such as
rheumatoid arthritis (17, 18). In addition to its direct effect on COX,
acetaminophen also inhibits prostaglandin synthesis by scavenging
peroxynitrite, an activator of COX (19).
Like nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen has both central and peripheral effects. Considerable evidence
supports a central effect of acetaminophen on prostaglandin synthesis, whereas a smaller number of studies show that it also inhibits
prostaglandin synthesis in the peripheral tissues. The first study to
show a central effect of acetaminophen was published in 1972 by
Flower and Vane (20). Subsequent studies show that acetaminophen
inhibits central prostaglandin E2 synthesis after administration of pyrogens or noxious peripheral stimulation (21–23). Acetaminophen
also effects prostaglandin synthesis in the peripheral tissues. For
example, administration of acetaminophen reduces prostaglandin
E2 release in the surgical sites after third molar extraction (24). Unlike NSAIDs, acetaminophen also inhibits myeloperoxidase and may
slow the development of diseases such as rheumatic disease and
atherosclerosis.
In addition to its effects on COX, the antinociceptive effects of acetaminophen are linked to endogenous neurotransmitter systems
including the opioid (25, 26), cannabinoid (27, 28), and
serotonergic systems (29, 30). Inhibitors of endogenous opioids,
endogenous cannabinoids, and serotonin (5-hydorxytryptamine) attenuate the antinociceptive effect of acetaminophen. The antinociceptive effects of acetaminophen may also be mediated via inhibition of
neurotransmitters in the central nervous system. For example, acetaminophen administration attenuates the nociceptive behavior elicited
by intrathecal administration of the neurotransmitters glutamate,
N-methyl-D-aspartate (NMDA), and substance P (31–33).
Another hypothesis for the analgesic effect of acetaminophen centers on its active metabolite AM404 (27). This is a brain-specific lipoamino acid that inhibits the production of prostaglandins, inhibits
allodynia in rats, and targets the ion channel TRPV1 (27, 34). It has
recently been shown that AM404 induces analgesia through a
supraspinal mechanism, namely TRPV1-dependent Cav3.2 current inhibition (35). Although these findings are exciting, the AM404 hypothesis
continues to be controversial because all current evidence is based on
rodent models.
Absorption
The absorption of acetaminophen after oral administration is from
the small intestine, and the rate of absorption depends on the rate of
gastric emptying. Food in the stomach and concomitant use of certain
other drugs such as opioids and anticholinergic agents may delay gastric
emptying (36–39). Caffeine accelerates the absorption of
acetaminophen (and decreases its clearance), which may account for
the increased analgesic effect noted when the 2 are taken together
(40). Acetaminophen has excellent bioavailability (z98%). Onset of
analgesia is about 30 minutes, and peak plasma concentrations are
reached within 30 to 60 minutes.
Distribution
The plasma protein binding of acetaminophen is low
(<25%); consequently, it is readily distributed throughout the
body (39). The ratio of concentrations in red blood cells and
plasma is 1.2:1 (41), which affects whole-body pharmacokinetics (42). Acetaminophen crosses both the blood-brain barrier
and (43) placental barrier (44, 45). Its plasma half-life is 1.5
to 2.5 hours (39).
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Disposition (Metabolism and Excretion)
Normally, acetaminophen undergoes hepatic conjugation by glucuronosyltransferase (20%–46%) and sulfotransferase (20%–46%)
into acetaminophen glucuronide and acetaminophen sulfate, respectively (39, 46). Glucuronidation, sulfation, and subsequent renal
excretion normally remove about 85%–90% of a therapeutic dose of
acetaminophen. However, after large doses of acetaminophen, these
pathways can become saturated.
About 10% of acetaminophen is normally metabolized by CYP450
isoenzymes 2E1 and, to a lesser extent, 1A2, 3A4, and 2A6. A product of
this pathway is the highly reactive metabolite N-acetyl-p-benzoquinone
imine (NAPQI). After large doses of acetaminophen or when the relevant CYP450 isoenzymes are induced by other drugs or chronic alcohol
consumption, NAPQI may accumulate in high concentrations (47–50).
Normally, NAPQI is detoxified into harmless metabolites by conjugation
of the sulfhydryl groups of glutathione by glutathione S-transferase into
mercapturic acid, which is eliminated in the urine (47, 50, 51).
However, glutathione can become depleted after large doses of
acetaminophen or in cases of malnutrition, allowing NAPQI to
accumulate. When this happens, NAPQI interacts covalently with liver
cell components, resulting in hepatic damage.
Therapeutic Considerations
The best evidence for the efficacy of analgesics comes from systematic reviews and meta-analysis of randomized double-blind controlled
trials (52–57). However, direct head-to-head trials are not always available. An alternative with direct clinical application is to calculate the
number needed to treat (NNT) (ie, the number of patients needed to
treat with drug A to achieve an improvement in outcome compared
with drug B for a treatment period of C) (58). The NNT always specifies
the comparator, the therapeutic outcome, and the duration of treatment
that is necessary to achieve the outcome. Analgesic efficacy expressed as
the NNT relates the number of patients who need to receive the active
drug for 1 patient to achieve at least 50% relief of pain compared
with placebo over a 4- to 6-hour treatment period (59). Consequently,
the NNT allows for the comparison of analgesics in the absence of headto-head trials.
In view of the decision by the FDA and the pharmaceutical industry
to formally withdraw from the market all prescription combination
analgesic formulations containing more than 325 mg acetaminophen,
it is relevant to review the analgesic efficacy of acetaminophen
(2-tablet or 2-capsule doses may still be prescribed, if appropriate)
vis-a-vis other available analgesic options. To this end, the Oxford
league table of analgesic efficacy (Table 1), predicated on the NNT, is
a useful resource. Internal validation of the Oxford league table of analgesic efficacy is provided by indirect comparisons of dose-response relationships. In all cases, higher doses provide better analgesia and lower
NNTs (55, 59–63). External validation of the Oxford league table of
analgesic efficacy is predicated on a systematic review that compared
acetaminophen and NSAIDs in head-to-head trials and found that
NSAIDs were consistently better than 1000 mg acetaminophen in dental
pain models (64).
Satisfactory relief of odontogenic pain can be attained through an
approach that incorporates disease-modifying procedures (ie, primary
dental care) and, when indicated, the administration of a diseasemodifying analgesic. Disease-modifying analgesics not only modulate
chemical activator–induced nociception, but they also have antiinflammatory properties affecting vascular tone and permeability, leukocyte recruitment, and the synthesis of cytokines. Based on the NNT,
acetaminophen is the least effective analgesic available for the management of odontogenic pain. However, it is of note that a full dose of
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TABLE 1. The Modified Oxford League Table of Analgesic Efficacy (55, 59–63)
Analgesic
Dosage
NNT*
Confidence
interval
Ibuprofen
Naproxen sodium
Ibuprofen
Acetylsalicylic acid
Ibuprofen
Naproxen sodium
Acetaminophen
Acetylsalicylic acid
Acetaminophen
600/800 mg
550 mg
400 mg
1200 mg
200 mg
220 mg
1000 mg
600/650 mg
600/650 mg
1.7
2.7
2.5
2.4
2.7
3.4
3.8
4.4
4.6
1.4–2.3
2.3–3.3
2.4–2.7
1.9–3.2
2.5–2.9
2.4–5.8
3.4–4.4
4.0–4.9
3.9–5.5
NNT, number needed to treat.
*NNT calculated for the proportion of patients with at least 50% pain relief over 4 to 6 hours
compared with placebo in randomized, double-blind, single-dose studies in patients with moderate
to severe pain.
ibuprofen, and presumably naproxen, in combination with a full dose of
acetaminophen is more effective than either of the 2 drugs alone (64).
Because acetaminophen has a lower analgesic efficacy (65), there
has been a trend over recent years for combining an NSAID with acetaminophen for pain management (66–68). In particular, the
combination of acetaminophen and NSAIDS has been reported to be
effective in managing endodontic pain (67, 68). Systematic reviews
with meta-analysis evaluated the efficacy of the combination of paracetamol and an NSAID versus either drug alone in various acute pain
models and reported that a combination of acetaminophen and an
NSAID may offer superior analgesia compared with either drug alone
(63, 65, 69–71). Furthermore, recent meta-analysis and current
studies have shown that the concurrent administration of acetaminophen and an NSAID can reduce postoperative opioid requirements
(63, 71–73).
Allergies
On January 13, 2014, the US FDA instructed manufacturers to add
to the label of all prescription drug products that contain acetaminophen a warning highlighting the potential for allergic reactions characterized by swelling of the face, mouth, and throat; difficulty breathing;
and itching and/or a rash (9). The same communication also warns
about rare cases of anaphylaxis with the use of acetaminophen. On
August 1, 2013, the FDA also warned that acetaminophen has been associated with a risk of rare but serious skin reactions (ie, Stevens-Johnson
syndrome and toxic epidermal necrolysis) (74). The FDA warns that
these reactions can occur with first-time use or at any time while acetaminophen is being taken. These skin reactions, which can be fatal, are
characterized by reddening of the skin, a rash, blisters, and detachment
of the upper surface of the skin (75, 76).
Asthma
A systematic review of the literature concluded that there is an
increased risk of asthma and wheezing in both children and adults
exposed to acetaminophen (77). The International Study of Asthma and
Allergies in Childhood provides evidence that acetaminophen intake during early infancy is linked to increased risk of rhinitis, asthma, wheeze, and
bronchial responsiveness in adolescents and in adults (78). Prenatal
exposure to acetaminophen is also associated with an increased risk of
asthma (79, 80). Cross-sensitivity between aspirin and acetaminophen
in aspirin-sensitive asthmatic patients has been reported with frequencies
ranging up to 34% (81). The prevalence and severity of asthma caused by
acetaminophen exposure have been estimated to be 20%–40% (82–84).
Because acetaminophen is used extensively in children for the treatment of
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Aminoshariae and Khan
pain and fever, some experts warn about its use in children with asthma or
at risk of asthma (82).
Liver Damage
Acetaminophen is the leading cause of acute liver failure in the
United States, and nearly 50% of acetaminophen-related cases are the
result of an unintentional overdose (4–6, 85).
Nausea, vomiting, anorexia, diarrhea, and abdominal pain occur
during the first 24 hours. Clinical evidence of hepatic damage may be
noted in 2 to 6 days. Although most patients appear well in the first
3 days after ingestion, it is likely that the liver damage can be prevented
only in the first 24 hours (86). The hepatotoxic single dose of acetaminophen in healthy adults is between 23 to 30 regular-strength (325 mg)
doses; for children, it is 150 mg/kg (87). In patients with liver disease,
alcohol and malnutrition (even with therapeutic doses of acetaminophen) may enhance this toxicity (47). However, hepatic injury in regular users of alcohol, especially chronic alcoholics, with malnutrition
who take acetaminophen with therapeutic intent has been reported
because of susceptibility by induction of cytochrome P450 2EI by
ethanol and depletion of glutathione (88).
However, APAP is still the preferred analgesic in patients with liver
disease because of the absence of platelet impairment associated with
NSAIDs (47). In general, NSAIDs should be avoided in patients with liver
disease (89). Although no consensus has been reached on what is a safe
dose, the total daily dose should not increase 2 g for patients with liver
damage (89, 90). Acetaminophen remains the drug of choice for these
patients (91–94).
A recent publication reported that acetaminophen-induced liver
toxicity depends on transient receptor potential melanostatine 2
(TRPM2) cation channels in hepatocytes, which are activated in response
to oxidative stress and are responsible for Ca2+ overload (95). The authors reported that a lack of TRPM2 channels in hepatocytes or their
pharmacologic inhibition protected the liver from acetaminophen
toxicity, and, thus, TRPM2 may serve as a potential therapeutic target.
Pregnancy
Acetaminophen is commonly taken during pregnancy for the treatment of pain and fever because it is safer than other over-the-counter
analgesics such as ibuprofen. Recent publications increasingly report
second-generation adverse effects of acetaminophen given in therapeutic doses. The use of acetaminophen during pregnancy is linked to
miscarriage, preterm birth, low birth weight, fetal malformations,
failure of neural development, and male infertility in the offspring
(96–98). Large cohort trials report an association between increased
frequency of acetaminophen use during pregnancy with the risk of
attention-deficit/hyperactivity disorder–like behavioral problems and
hyperkinetic disorders in children (97). A sibling-controlled cohort
study examined the effect of prenatal acetaminophen and ibuprofen
exposure in nearly 3000 same-sex siblings (98). Children exposed to
prenatal acetaminophen had poorer gross motor development and
communication and higher activity levels. Exposure to ibuprofen was
not associated with these neurodevelopmental outcomes.
Recent evidence suggests that acetaminophen is a hormone
disrupter (ie, it interferes with reproductive and thyroid hormone
function essential for normal brain development) (99–102).
Maternal intake of acetaminophen for more than 4 weeks during
pregnancy, especially during the first and second trimesters, may
moderately increase the occurrence of cryptorchidism (44). As
mentioned earlier, there may be also a causal relationship between
the use of acetaminophen during pregnancy and wheezing or asthma
in their offspring (103, 104).
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Drug-Drug Interactions
The FDA issued a warning about a potential drug-drug interaction
between acetaminophen and warfarin sodium (7). The warning is
based on 2 prospective, randomized, double-blind, placebo-controlled
studies, which have concluded that long-term concurrent use of acetaminophen (2–4 g daily for 4 weeks) with warfarin may increase the
international normalized ratio and the risk of bleeding (105, 106).
Hematologic Malignancies
An almost 2-fold increased risk of developing hematologic malignancies such as lymphomas and myelodysplastic syndrome has been reported in chronic users of acetaminophen ($4 days/week
for $4 years) (107–109).
Recent Developments
Acetaminophen is now available for intravenous injection with
some very promising results (13). The use of intravenous acetaminophen led to a decrease in the use of opioids as well as a shorter hospital
length of stay in surgery patients (110, 111). A postmarketing review of
300 patients who were given intravenous acetaminophen shows that it is
a safe and effective analgesic and antipyretic agent (112). A new buccal
form of acetaminophen may also be soon available. Two randomized
crossover clinical trials compared acetaminophen administered by
different routes (ie, intravenously, buccally, and submucosally) (113).
A faster onset of antinociception was noted with buccal acetaminophen
compared with the 2 other routes of administration. These studies were
performed in normal volunteers (and not in patients experiencing pain).
If buccal acetaminophen has similar effects in patients with odontogenic
pain, it may help improve pain management in endodontic patients.
Conclusion
Although acetaminophen is considered a safe drug with minimum
side effects, its mechanism of actions had been poorly understood until
now. While acetaminophen is generally considered a very safe drug,
there are no ‘‘absolutely’’ safe biologically active therapeutic agents
(ie, drugs seldom exert their beneficial effects without the potential
for also causing side effects). Even with therapeutic doses, acetaminophen can cause adverse drug events in certain conditions such as
chronic alcohol use, malnutrition, and polypharmacy (4). Indiscriminate consumption of acetaminophen can cause acute liver failure,
trigger hormone disruption in pregnant patients, increase the risk of
asthma in children, cause serious allergic reaction and toxicity, potentiate the effect of warfarin, and increase the risk of hematologic malignancies. To prevent these side effects, consumers and practitioners
need to be well informed and be aware of the total maximum recommended daily dose.
Acknowledgments
The authors would like to thank Dr Geza T. Terezhalmy for his
valuable comments.
The authors deny any conflicts of interest related to this study.
References
1. Guggenheimer J, Moore PA. The therapeutic applications of and risks associated with acetaminophen use: a review and update. J Am Dent Assoc 2011;
142:38–44.
2. FDA drug safety communication: prescription acetaminophen products to be
limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm239821.
htm. Accessed October 1, 2014.
JOE — Volume 41, Number 5, May 2015
3. Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute
liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;
137:947–54.
4. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure:
results of a United States multicenter, prospective study. Hepatology 2005;42:
1364–72.
5. Nourjah P, Ahmad SR, Karwoski C, Willy M. Estimates of acetaminophen (Paracetomal)-associated overdoses in the United States. Pharmacoepidemiol Drug Saf
2006;15:398–405.
6. Bower WA, Johns M, Margolis HS, et al. Population-based surveillance for acute
liver failure. Am J Gastroenterol 2007;102:2459–63.
7. Federal Register. 2009. Available at: http://www.gpo.gov/fdsys/pkg/FR-2009-0429/pdf/E9-9817.pdf. Accessed October 1, 2014.
8. Food and Drug Administration (FDA). 2009. Available at: http://www.accessdata.
fda.gov/scripts/cdrh/cfdocs/psn/transcript.cfm?show=87#9. Accessed October 1,
2014.
9. Food Drug Administration. All manufacturers of prescription combination
drug products with more than 325 mg of acetaminophen have discontinued
marketing. Available at: http://www.fda.gov/Drugs/DrugSafety/Informationby
DrugClass/ucm390509.htm. Accessed October 1, 2014.
10. Krenzelok EP. The FDA Acetaminophen Advisory Committee Meeting—what is the
future of acetaminophen in the United States? The perspective of a committee member. Clin Toxicol (Phila) 2009;47:784–9.
11. Krenzelok EP, Royal MA. Confusion: acetaminophen dosing changes based on NO
evidence in adults. Drugs R D 2012;12:45–8.
12. McNeil-PPC. Tylenol Regular Strength (acetaminophen) tablet. McNeil Consumer healthcare Div; 2013. Available at: http://dailymed.nlm.nih.gov/dailymed/
lookup.cfm?setid=1622f694-4d63-4c56-8737-fae31f0ecfb7. Accessed October
1, 2014.
13. OFIRMEV. Available at: http://www.ofirmev.com/. Accessed October 1, 2014.
14. Smith HS. Potential analgesic mechanisms of acetaminophen. Pain Physician 2009;
12:269–80.
15. Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Pediatr
Anesth 2008;18:915–21.
16. Nomura DK, Morrison BE, Blankman JL, et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 2011;334:
809–13.
17. Hanel AM, Lands WE. Modification of anti-inflammatory drug effectiveness by
ambient lipid peroxides. Biochem Pharmacol 1982;31:3307–11.
18. Boutaud O, Aronoff DM, Richardson JH, et al. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H2 synthases. Proc Natl
Acad Sci U S A 2002;99:7130–5.
19. Schildknecht S, Daiber A, Ghisla S, et al. Acetaminophen inhibits prostanoid synthesis by scavenging the PGHS-activator peroxynitrite. FASEB J 2008;22:215–24.
20. Flower RJ, Vane JR. Inhibition of prostaglandin synthetase in brain explains the
anti-pyretic activity of paracetamol (4-acetamidophenol). Nature 1972;240:
410–1.
21. Feldberg W, Gupta K. Pyrogen fever and prostaglandin-like activity in cerebrospinal
fluid. J Physiol 1973;228:41–53.
22. Muth-Selbach US, Tegeder I, Brune K, Geisslinger G. Acetaminophen inhibits spinal
prostaglandin E2 release after peripheral noxious stimulation. Anesthesiology
1999;91:231–9.
23. Ayoub SS, Botting RM, Goorha S, et al. Acetaminophen-induced hypothermia in
mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein. Proc Natl Acad Sci U S A 2004;101:11165–9.
24. Lee YS, Kim H, Brahim JS, et al. Acetaminophen selectively suppresses peripheral
prostaglandin E2 release and increases COX-2 gene expression in a clinical model
of acute inflammation. Pain 2007;129:279–86.
25. Marek G, Aghajanian G. 5-Hydroxytryptamine-induced excitatory postsynaptic currents in neocortical layer V pyramidal cells: suppression by [mu]-opiate receptor
activation. Neuroscience 1998;86:485–97.
26. Ruggieri V, Vitale G, Pini LA, Sandrini M. Differential involvement of opioidergic
and serotonergic systems in the antinociceptive activity of N-arachidonoyl-phenolamine (AM404) in the rat: comparison with paracetamol. Naunyn Schmiedebergs
Arch Pharmacol 2008;377:219–29.
27. H€ogest€att ED, J€onsson BA, Ermund A, et al. Conversion of acetaminophen to the
bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent
arachidonic acid conjugation in the nervous system. J Biol Chem 2005;280:
31405–12.
28. Dani M, Guindon J, Lambert C, Beaulieu P. The local antinociceptive effects of
paracetamol in neuropathic pain are mediated by cannabinoid receptors. Eur J
Pharmacol 2007;573:214–5.
29. Pelissier T, Alloui A, Caussade F, et al. Paracetamol exerts a spinal antinociceptive
effect involving an indirect interaction with 5-hydroxytryptamine3 receptors:
in vivo and in vitro evidence. J Pharmacol Exp Ther 1996;278:8–14.
Acetaminophen Old Drug, New Issues
591
Review Article
30. Pini LA, Sandrini M, Vitale G. The antinociceptive action of paracetamol is associated with changes in the serotonergic system in the rat brain. Eur J Pharmacol
1996;308:31–40.
31. Choi SS, Lee JK, Suh HW. Antinociceptive profiles of aspirin and acetaminophen in
formalin, substance P and glutamate pain models. Brain Res 2001;921:233–9.
32. Crawley B, Saito O, Malkmus S, et al. Acetaminophen prevents hyperalgesia in central pain cascade. Neurosci Lett 2008;442:50–3.
33. Bj€orkman R, Hallman K, Hedner J, et al. Acetaminophen blocks spinal hyperalgesia
induced by NMDA and substance P. Pain 1994;57:259–64.
34. Zygmunt PM, Chuang H, Movahed P, et al. The anandamide transport inhibitor
AM404 activates vanilloid receptors. Eur J Pharmacol 2000;396:39–42.
35. Kerckhove N, Mallet C, François A, et al. Cav3.2 calcium channels: the key protagonist in the supraspinal effect of paracetamol. Pain 2014;155:764–72.
36. McGilveray I, Mattok G. Some factors affecting the absorption of paracetamol.
J Pharm Pharmacol 1972;24:615–9.
37. Nimmo W, Heading R, Wilson J, et al. Inhibition of gastric emptying and drug absorption by narcotic analgesics. Br J Clin Pharmacol 1975;2:509–13.
38. Nimmo J, Heading R, Tothill P, Prescott L. Pharmacological modification of gastric
emptying: effects of propantheline and metoclopromide on paracetamol absorption. Br Med J 1973;1:587–9.
39. Prescott L. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol 1980;10:291S–8.
40. Renner B, Clarke G, Grattan T, et al. Caffeine accelerates absorption and enhances
the analgesic effect of acetaminophen. J Clin Pharmacol 2007;47:715–26.
41. Gazzard B, Ford-Hutchinson A, Smith M, Williams R. The binding of paracetamol to
plasma proteins of man and pig. J Pharm Pharmacol 1973;25:964–7.
42. Hinderling PH. Red blood cells: a neglected compartment in pharmacokinetics
and pharmacodynamics. Pharmacol Rev 1997;49:279–95.
43. Mallet C, Barriere DA, Ermund A, et al. TRPV1 in brain is involved in
acetaminophen-induced antinociception. PLoS One 2010;5:e12748.
44. Jensen MS, Rebordosa C, Thulstrup AM, et al. Maternal use of acetaminophen,
ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism.
Epidemiology 2010;21:779–85.
45. Mazaud-Guittot S, Nicolaz CN, Desdoits-Lethimonier C, et al. Paracetamol, aspirin,
and indomethacin induce endocrine disturbances in the human fetal testis capable
of interfering with testicular descent. J Clin Endocrinol Metab 2013;98:E1757–67.
46. Forrest JA, Clements J, Prescott L. Clinical pharmacokinetics of paracetamol. Clin
Pharmacokinet 1982;7:93–107.
47. Benson GD, Koff RS, Tolman KG. The therapeutic use of acetaminophen in patients
with liver disease. Am J Ther 2005;12:133–41.
48. Potter W, Davis D, Mitchell J, et al. Acetaminophen-induced hepatic necrosis. III.
Cytochrome P-450-mediated covalent binding in vitro. J Pharmacol Exp Ther
1973;187:203–10.
49. Jollow DJ, Thorgeirsson S-S, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. VI. Metabolic disposition of toxic and nontoxic doses of acetaminophen.
Pharmacology 1973;12:251–71.
50. Potter W, Thorgeirsson S, Jollow D, Mitchell J. Acetaminophen-induced hepatic
necrosis V. Correlation of hepatic necrosis, covalent binding and glutathione
depletion in hamsters. Pharmacology 1974;12:129–43.
51. Mitchell JR, Thorgeirsson SS, Potter WZ, et al. Acetaminophen-induced hepatic
injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther 1974;16:676–84.
52. Moore A, Collins S, Carroll D, McQuay H. Paracetamol with and without codeine in
acute pain: a quantitative systematic review. Pain 1997;70:193–201.
53. Moore A, Collins S, Carroll D, et al. Single dose paracetamol (acetaminophen),
with and without codeine, for postoperative pain. Cochrane Database Syst Rev
2000;2:CD001547.
54. Barden J, Edwards J, Moore A, McQuay H. Single dose oral paracetamol (acetaminophen) for postoperative pain. Cochrane Database Syst Rev 2004;1:
CD004602.
55. Mason L, Edwards JE, Moore RA, McQuay HJ. Single-dose oral naproxen for acute
postoperative pain: a quantitative systematic review. BMC Anesthesiol 2003;3:4.
56. Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane Database Syst Rev 2008;4:
CD004602.
57. Toms L, Derry S, Moore RA, McQuay HJ. Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults. Cochrane Database Syst Rev
2009;1:CD001547.
58. McQuay HJ, Moore RA. Using numerical results from systematic reviews in clinical
practice. Ann Intern Med 1997;126:712–20.
59. Acute pain Bandolier—evidenced based health care. Available at: http://www.
medicine.ox.ac.uk/bandolier/Extraforbando/APain.pdf. Accessed October 1, 2014.
60. Bandolier—evidenced based health care. Available at: http://www.medicine.ox.ac.
uk/bandolier/booth/painpag/Acutrev/Analgesics/AP028.html. Accessed October 1,
2014.
592
Aminoshariae and Khan
61. Krisanaprakornkit S, Kimball JR, Dale BA. Regulation of human b-defensin-2 in
gingival epithelial cells: the involvement of mitogen-activated protein kinase pathways, but not the NF-kB transcription factor family. J Immunol 2002;168:316–24.
62. Moore RA. Bandolier’s Little Book of Pain. New York: Oxford University Press;
2003.
63. Moore PA, Hersh EV. Combining ibuprofen and acetaminophen for acute pain
management after third-molar extractions: translating clinical research to dental
practice. J Am Dent Assoc 2013;144:898–908.
64. Hyllested M, Jones S, Pedersen J, Kehlet H. Comparative effect of paracetamol,
NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 2002;88:199–214.
65. Bailey E, Worthington H, Coulthard P. Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth, a Cochrane
systematic review. Br Dent J 2014;216:451–5.
66. Bailey E, Worthington HV, van Wijk A, et al. Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth. Cochrane
Database Syst Rev 2013;12:CD004624.
67. Menhinick K, Gutmann J, Regan J, et al. The efficacy of pain control following
nonsurgical root canal treatment using ibuprofen or a combination of ibuprofen
and acetaminophen in a randomized, double-blind, placebo-controlled study. Int
Endod J 2004;37:531–41.
68. Wells LK, Drum M, Nusstein J, et al. Efficacy of ibuprofen and ibuprofen/acetaminophen on postoperative pain in symptomatic patients with a pulpal diagnosis of
necrosis. J Endod 2011;37:1608–12.
69. Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen)
with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg 2010;110:1170–9.
70. Derry CJ, Derry S, Moore RA. Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain. Cochrane Database Syst Rev 2013;6:
CD010210.
71. Elia N, Lysakowski C, Tramer MR. Does multimodal analgesia with acetaminophen,
nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and
patient-controlled analgesia morphine offer advantages over morphine alone?:
meta-analyses of randomized trials. Anesthesiology 2005;103:1296–304.
72. Merry A, Gibbs R, Edwards J, et al. Combined acetaminophen and ibuprofen for
pain relief after oral surgery in adults: a randomized controlled trial. Br J Anaesth
2010;104:80–8.
73. Mehlisch DR, Ashley S, Daniels SE, Bandy DP. Comparison of the analgesic efficacy
of concurrent ibuprofen and paracetamol with ibuprofen or paracetamol alone in
the management of moderate to severe acute postoperative dental pain in adolescents and adults: a randomized, double-blind, placebo-controlled, parallel-group,
single-dose, two-center, modified factorial study. Clin Ther 2010;32:882–95.
74. FDA. FDA warns of rare but serious skin reactions with the pain reliever/fever
reducer acetaminophen. Available at: http://www.fda.gov/drugs/drugsafety/ucm
363041.htm. Accessed October 1, 2014.
75. Kim EJ, Lim H, Park SY, et al. Rapid onset of Stevens-Johnson syndrome and toxic
epidermal necrolysis after ingestion of acetaminophen. Asia Pac Allergy 2014;4:
68–72.
76. Kuehn BM. FDA: acetaminophen may trigger serious skin problems. JAMA 2013;
310:785.
77. Etminan M, Sadatsafavi M, Jafari S, et al. Acetaminophen use and the risk of asthma
in children and adults: a systematic review and metaanalysis. Chest 2009;136:
1316–23.
78. Beasley R, Clayton T, Crane J, et al. Association between paracetamol use in infancy
and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children
aged 6–7 years: analysis from phase three of the ISAAC programme. Lancet
2008;372:1039–48.
79. Shaheen SO, Newson RB, Ring SM, et al. Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma. J Allergy Clin
Immunol 2010;126:1141–11487.
80. Eyers S, Weatherall M, Jefferies S, Beasley R. Paracetamol in pregnancy and the risk
of wheezing in offspring: a systematic review and meta-analysis. Clin Exp Allergy
2011;41:482–9.
81. Settipane RA, Schrank PJ, Simon RA, et al. Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects. J Allergy Clin Immunol 1995;
96:480–5.
82. Beasley RW, Clayton TO, Crane J, et al. Acetaminophen use and risk of asthma,
rhinoconjunctivitis, and eczema in adolescents: International Study of Asthma
and Allergies in Childhood Phase Three. Am J Respir Crit Care Med 2011;183:
171–8.
83. Amberbir A, Medhin G, Alem A, et al. The role of acetaminophen and geohelminth
infection on the incidence of wheeze and eczema: a longitudinal birth-cohort
study. Am J Respir Crit Care Med 2011;183:165–70.
84. McBride JT. The association of acetaminophen and asthma prevalence and
severity. Pediatrics 2011;128:1181–5.
JOE — Volume 41, Number 5, May 2015
Review Article
85. Lai MW, Klein-Schwartz W, Rodgers GC, et al. 2005 Annual Report of the American
Association of Poison Control Centers’ national poisoning and exposure database.
Clin Toxicol 2006;44:803–932.
86. Clark R, Borirakchanyavat V, Davidson A, et al. Hepatic damage and death from
overdose of paracetamol. Lancet 1973;301:66–70.
87. Acetaminophen safety - deja vu. Med Lett Drugs Ther 2009;51:53–4. 56.
88. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with
regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995;22:767–73.
89. Riley T 3rd, Bhatti AM. Preventive strategies in chronic liver disease: part I.
Alcohol, vaccines, toxic medications and supplements, diet and exercise. Am
Fam Physician 2001;64:1555–60.
90. Schilling A, Corey R, Leonard M, Eghtesad B. Acetaminophen: old drug, new warnings. Cleve Clin J Med 2010;77:19–27.
91. Prescott L. Effects of non-narcotic analgesics on the liver. Drugs 1986;32:129–47.
92. Jones AL. Recent advances in the management of late paracetamol poisoning.
Emerg Med 2000;12:14–21.
93. O’connor N, Dargan PI, Jones AL. Hepatocellular damage from non-steroidal antiinflammatory drugs. QJM 2003;96:787–91.
94. Graham GG, Davies MJ, Day RO, et al. The modern pharmacology of paracetamol:
therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology 2013;21:201–32.
95. Kheradpezhouh E, Ma L, Morphett A, et al. TRPM2 channels mediate
acetaminophen-induced liver damage. Proc Natl Acad Sci U S A 2014;111:
3176–81.
96. Thiele K, Kessler T, Arck P, et al. Acetaminophen and pregnancy: short-and
long-term consequences for mother and child. J Reprod Immunol 2013;97:
128–39.
97. Liew Z, Ritz B, Rebordosa C, et al. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr 2014;168:313–20.
98. Brandlistuen RE, Ystrom E, Nulman I, et al. Prenatal paracetamol exposure and
child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol
2013;42:1702–13.
99. Albert O, Desdoits-Lethimonier C, Lesne L, et al. Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis
in vitro. Hum Reprod 2013;28:1890–8.
JOE — Volume 41, Number 5, May 2015
100. Colborn T. Neurodevelopment and endocrine disruption. Environ Health Perspect
2004;112:944–9.
101. Howdeshell KL. A model of the development of the brain as a construct of the thyroid system. Environ Health Perspect 2002;110:337–48.
102. Rubinow DR, Schmidt PJ. Androgens, brain, and behavior. Am J Psychiatry 1996;
153:974–84.
103. Shaheen S, Newson R, Sherriff A, et al. Paracetamol use in pregnancy and wheezing
in early childhood. Thorax 2002;57:958–63.
104. Scialli AR, Ang R, Breitmeyer J, Royal MA. Childhood asthma and use during pregnancy of acetaminophen. A critical review. Reprod Toxicol 2010;30:508–19.
105. Parra D, Beckey NP, Stevens GR. The effect of acetaminophen on the international
normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy
2007;27:675–83.
106. Mahe I, Bertrand N, Drouet L, et al. Interaction between paracetamol and warfarin
in patients: a double-blind, placebo-controlled, randomized study. Haematologica
2006;91:1621–7.
107. Walter RB, Milano F, Brasky TM, White E. Long-term use of acetaminophen,
aspirin, and other nonsteroidal anti-inflammatory drugs and risk of hematologic
malignancies: results from the prospective Vitamins and Lifestyle (VITAL) study.
J Clin Oncol 2011;29:2424–31.
108. Robak P, Smolewski P, Robak T. The role of non-steroidal anti-inflammatory drugs
in the risk of development and treatment of hematologic malignancies. Leuk Lymphoma 2008;49:1452–62.
109. Becker N, Fortuny J, Alvaro T, et al. Medical history and risk of lymphoma: results
of a European case–control study (EPILYMPH). J Cancer Res Clin Oncol 2009;135:
1099–107.
110. Herring BO, Ader S, Maldonado A, et al. Impact of intravenous acetaminophen on
reducing opioid use after hysterectomy. Pharmacotherapy 2014;34:27S–33.
111. Smith AN, Hoefling VC. A retrospective analysis of intravenous acetaminophen use
in spinal surgery patients. Pharm Pract (Granada) 2014;12:417.
112. Hall NS, Le B. Postmarketing review of intravenous acetaminophen dosing based
on Food and Drug Administration prescribing guidelines. Pharmacotherapy
2014;34:34S–9.
113. Pickering G, Macian N, Libert F, et al. Buccal acetaminophen provides fast analgesia: two randomized clinical trials in healthy volunteers. Drug Des Devel Ther
2014;8:1621–7.
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