"The US Food and Drug Administration (FDA) has approved diclofenac sodium injection (Dyloject, Hospira Inc), a proprietary nonsteroidal anti-inflammatory drug (NSAID) for the treatment of mild to moderate pain, and for the management of mod"...
Acetaminophen is an analgesic and antipyretic agent and has been clinically proven to be effective for the temporary relief of minor aches and pains associated with the common cold, headache, toothache, muscular aches, backache, for the minor pain of arthritis, for the pain of menstrual cramps, and for the reduction of fever. Acetaminophen is an effective antipyretic in infants, children, and adults.
b. Pharmacologic Class
Acetaminophen is a centrally acting analgesic and antipyretic agent.
c. Mechanism of Action
Although the exact site and mechanism of analgesic action is not clearly defined, acetaminophen appears to produce analgesia by elevation of the pain threshold.2-4 The potential mechanism may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate and substance P.5
Investigations indicate that endogenous pyrogens produced by leukocytes cause an elevation of prostaglandin E (PGE) in the cerebrospinal fluid. Fever results when the elevated PGE acts on the preoptic area of the anterior hypothalamus to decrease heat loss and increase heat gain. Acetaminophen has been shown to inhibit the action of endogenous pyrogens on the heat-regulating centers in the brain by blocking the formation and release of prostaglandins in the central nervous system.6-9 Inhibition of arachidonic acid metabolism is not requisite for the antipyretic effect of acetaminophen.10 Acetaminophen does not depend upon the activation of the arginine vasopressin V-1 receptor to induce antipyresis as has been noted in rats treated with indomethacin and salicylates.11,12 This has been demonstrated in animals by observing a decrease in both fever and PGE activity following administration of acetaminophen to unanesthetized cats, and in rabbits and dogs when brain prostaglandin synthetase was inhibited by the administration of acetaminophen.13,14
d. Pharmacokinetic Data
Oral acetaminophen is rapidly and almost completely absorbed from the gastrointestinal tract primarily in the small intestine. This absorption process occurs by passive transport. The relative bioavailability ranges from 85% to 98%.15
Figure 1 shows the mean pharmacokinetic profile for 24 fasting subjects who received acetaminophen 1000 mg dosed as liquid or caplets. For individual subjects, maximal plasma concentrations occurred within 10 to 90 minutes following ingestion and ranged from 8 to 32 µg/mL. Acetaminophen plasma concentrations range from 1 to 4 µg/mL 6 hours after ingestion.
Each bilayered acetaminophen extended-release, 650-mg caplet contains 325 mg of immediate-release acetaminophen on one side and, on the other side, 325 mg of acetaminophen in a matrix formulation designed to slowly release. In vitro data indicate that two 650-mg extended-release caplets
FIGURE 1. Mean plasma concentrations of acetaminophen in 24 male subjects following oral administration of 1000 mg of acetaminophen dosed as either 30 mL of Extra Strength TYLENOL® acetaminophen Adult Liquid Pain Reliever or as two Extra Strength TYLENOL® acetaminophen Caplets.
FIGURE 2. Mean plasma concentrations of acetaminophen in 24 male subjects following oral administration of 1300 mg acetaminophen dosed as either two caplets of TYLENOL® (acetaminophen) Arthritis Extended Relief or four Regular Strength TYLENOL® acetaminophen (two caplets given at 0 and 4 hours).
(containing a total of 1300 mg of acetaminophen) release 88% and 95% of the drug within 3 and 5 hours, respectively.16 Following administration of a single dose of two 650-mg, extended-release caplets, the average maximal plasma concentrations occurred within 0.5 to 3 hours following ingestion and ranged from 6.9 to 14.1 µg/mL. Figure 2 shows the mean pharmacokinetic profile for 24 fasting subjects who received acetaminophen 1300 mg dosed as two extended-release or four regular-strength caplets (two caplets given at 0 and 4 hours).
Acetaminophen appears to be widely distributed throughout most body fluids except fat. The apparent volume of distribution of acetaminophen is 0.95 L/kg.17 A relatively small proportion (10% to 25%) of acetaminophen is bound to plasma proteins and binding is only slightly increased in plasma concentrations associated with overdose.18,19 The sulfate and glucuronide metabolites do not bind to plasma proteins even at relatively high concentrations.20
Low protein binding and low molecular weight allow acetaminophen to pass through the blood-brain barrier. The peak concentration of acetaminophen in cerebrospinal fluid is reached after 2 to 3 hours.21,22
Analysis of urine samples has demonstrated the passage of unconjugated acetaminophen via placental transfer.23 When given to the mother in therapeutic doses, acetaminophen crosses the placenta into fetal circulation as early as 30 minutes after ingestion, although the difference in serum concentration between maternal and cord blood is not statistically significant.24 In the fetus, acetaminophen is effectively metabolized by sulfate conjugation.25
Maternal ingestion of acetaminophen in recommended analgesic doses does not present a risk to the nursing infant. Amounts in milk range from 0.1% to 1.85% of the ingested maternal dose.26-28 These studies have established that, even at the time of peak acetaminophen concentration in human breast milk, the nursing infant would receive less than 2% of the maternal dose. Accordingly, breast feeding need not be interrupted because of maternal ingestion of recommended doses of acetaminophen.
Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways:
a) conjugation with glucuronide
b) conjugation with sulfate
c) oxidation via the cytochrome, P450-dependent, mixed-function oxidative enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates.29 The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways.30-32
Two additional minor pathways also are possibly involved in acetaminophen metabolism:33
a) hydroxylation to form 3-hydroxy-acetaminophen
b) methoxylation to form 3-methoxy-acetaminophen.
These metabolites are further conjugated with glucuronide or sulfate.
In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity.8 In premature infants, newborns, and young infants, the sulfate conjugate predominates.23,34
The biologic half-life of acetaminophen in normal adults is approximately 2 to 3 hours in the usual dosage range.21,35 It is somewhat shorter in children and somewhat longer in neonates and in patients with cirrhosis.18 The elimination half-life is approximately 3 hours for the extended-release product. The elimination half-life of acetaminophen in the cerebrospinal fluid according to pooled data is 3.2 hours.21
Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Table 1 0n the following page shows the mean range of acetaminophen urinary metabolite values in healthy subjects using therapeutic doses (10 mg/kg or 1000-mg dose).36-40 Less than 9% of acetaminophen is excreted unchanged in the urine.37
TABLE 1. Acetaminophen metabolites found in urine
| Range of mean
|Glucuronide||46.8 - 62.2|
|Sulfate||25.4 - 35.9|
|Mercapturate||2.7 - 5.0|
|Cysteine conjugate||2.1 - 3.0|
|Free acetaminophen||3.4 - 8.7|
TABLE 2. Adult TYLENOL® acetaminophen preparations
|Preparation||Strength||Adult single dose||Frequencya|
|Regular Strength TYLENOL|
|Tablets/Caplets||325 mg||650 mg||Every 4 to 6 hb|
|Extra Strength TYLENOL|
|Tablets/Caplets/Gelcaps/Geltabs||500 mg||1000 mg||Every 4 to 6 hc,d|
|Adult Liquid||500 mg/15 mL||1000 mg||Every 4 to 6 hd,e|
|TYLENOL Arthritis Extended Relief Caplets||650 mg||1300 mg||Every 8 hd,f|
| a Not to exceed 4000 mg in any 24-hour period.
b Not to exceed 12 tablets per day.
c Not to exceed 8 tablets per day
d Not for use in children under 12 years of age.
e Not to exceed 8 tablespoons per day.
f Not to exceed 6 caplets per day.
TABLE 3. Pediatric TYLENOL® acetaminophen preparations
|Infants'TYLENOL Concentrated Drops||80 mg/0.8 mL|
|Children's TYLENOL Elixir||160 mg/5 mL|
|Children's TYLENOL Suspension Liquid||160 mg/5 mL|
|Children's TYLENOL Chewable Tablets||80 mg|
|Junior Strength TYLENOL Chewable Tablets||160 mg|
|Junior Strength TYLENOL Caplets||160 mg|
|a Dosing to be based on age or weight (approximately 10-15 mg/kg/dose; not to exceed 5 doses in 24 hours).|
Other minor metabolites, each accounting for 4% or less of a therapeutic dose, include sulfate and glucuronide conjugates of 3-methoxy-acetaminophen, 3-hydroxy-acetaminophen, and 3-methyl-thioacetaminophen.39,41-43 Slight differences have been seen in ethnically distinct populations (eg, Asian, Spanish).36,44-46
Clinical Studies: Therapeutic Comparisons With Other Drugs Or Treatments
In controlled trials, acetaminophen was shown to be superior to placebo.53-56 Tepid sponging and acetaminophen have been shown to be approximately equivalent for the initial 30 minutes of treatment, after which acetaminophen is superior. The combination of acetaminophen and sponging may provide additive benefit, but at the expense of additional discomfort to the child.54,56. There is no significant difference in antipyresis between equivalent doses of aspirin and acetaminophen. 51,52,57,58 Comparative clinical studies of the antipyretic efficacy of acetaminophen and ibuprofen administered in recommended dosages to pediatric patients suggest that both drugs are effective.59-62 However, results vary depending on the dosage of each agent administered. Acetaminophen at a dose of 15 mg/kg is equivalent to ibuprofen at a dose of 10 mg/kg.60 Acetaminophen 10 mg/kg or 12.5 mg/kg does not produce the same degree of antipyresis as ibuprofen 7.5 mg/kg or 10 mg/kg.59,61,62 Acetaminophen 12.5 mg/kg is superior to ibuprofen 5 mg/kg.63 In these studies, onset of antipyresis with acetaminophen generally occurred within 30 to 60 minutes following administration and peak antipyresis was noted at 2 to 3 hours.
Acetaminophen is effective in the treatment of various disorders associated with pain of mild to moderate intensity. Studies have been performed in a variety of pain models to assess the overall efficacy of acetaminophen. Clinical research has substantiated efficacy in pain associated with the following conditions:
At recommended dosages, acetaminophen is well tolerated and effective for the treatment of minor pain of arthritis. Clinical studies have compared the efficacy of acetaminophen to placebo, ibuprofen, and naproxen in patients with osteoarthritis of the knee.48-50 In a double-blind, placebo-controlled study, Amadio and Cummings48 found that 1000 mg of acetaminophen administered four times daily was significantly more effective than placebo in relieving tenderness, pain at rest, and pain on motion. In a randomized, double-blind study comparing acetaminophen (4000 mg/d) with analgesic (1200 mg/d) and anti-inflammatory (2400 mg/d) doses of ibuprofen, Bradley and colleagues49 reported that acetaminophen was comparable to both doses of ibuprofen in relieving pain. In a double-blind study lasting up to 2 years that compared the relative safety and efficacy of acetaminophen (2600 mg/d) to naproxen (750 mg/d), Williams and associates50 noted that acetaminophen was similar to naproxen in improving pain on motion and in physicians' global assessment of disease activity.
Acetaminophen taken for 1 month to 2 years is beneficial in relieving osteoarthritic pain and causes no significant adverse effects. American College of Rheumatology* Guidelines for the Medical Management of Osteoarthritis, published in 1995, recommend acetaminophen in doses up to 4000 mg daily as the preferred first-line therapy in patients with symptomatic osteoarthritis of the knee.64
Three randomized, multicenter, double-blind, single-dose, placebo-controlled studies have been conducted by McNeil (unpublished), which evaluated the efficacy of acetaminophen in the tension headache model. In the first study, patients were treated with acetaminophen 1000 mg, ibuprofen 200 mg, ibuprofen 400 mg, or placebo. The active treatments were more effective than placebo, and neither strength of ibuprofen was different from acetaminophen; however, ibuprofen 400 mg was significantly more effective than ibuprofen 200 mg in patients' overall evaluation. The second study compared the efficacy of acetaminophen 1000 mg, naproxen 375 mg, and placebo. Acetaminophen and naproxen were rated significantly higher than placebo but were not different from each other. The third study evaluated acetaminophen 1000 mg, naproxen sodium 440 mg, and placebo. Both active treatments were significantly better than placebo. Naproxen sodium was significantly more effective than acetaminophen for patients with baseline pain of moderate severity. However, comparisons of patients with severe baseline pain were not significantly different between the active treatment groups.
Post-Oral Surgery Pain
Several dose-ranging studies have assessed the efficacy of acetaminophen in post-oral surgery pain.
Two double-blind, single-dose studies (unpublished) evaluated patients who had undergone oral surgery and were experiencing moderate to severe pain. In these studies, acetaminophen 650 mg and 1000 mg was superior to placebo in all summary measures for moderate pain. For more severe pain, acetaminophen 1000 mg was superior to acetaminophen 650 mg. In two randomized studies, acetaminophen 2000 mg did not provide greater analgesia compared with acetaminophen 1000 mg.65,66
Three studies (unpublished) compared the relative analgesic efficacy of acetaminophen, aspirin, and placebo in patients experiencing pain following dental surgery. Two double-blind, single-dose studies demonstrated that acetaminophen 975 mg and 1000 mg were significantly better than aspirin 650 mg in relieving pain. In a third study, acetaminophen 1000 mg and aspirin 1000 mg were significantly more effective than placebo but were not different from each other.
Several studies have compared the analgesic efficacy of acetaminophen and ibuprofen following dental surgery. Most studies showed that both active treatments were effective compared with placebo, but in some studies ibuprofen 400 mg provided greater pain relief than acetaminophen 1000 mg in patients with moderate to severe baseline pain.67,68
In another study, patients were randomized to receive 500 mg of diflunisal or 1000 mg of acetaminophen prior to oral surgery. Both treatments were effective and the difference in mean overall pain scores between the two regimens was not significantly different.69
Quiding and colleagues70 evaluated the analgesic efficacy of a two-dose regimen of codeine 60 mg compared with acetaminophen 1000 mg in patients undergoing surgical removal of a third molar tooth. Acetaminophen 500 mg was used as the control. After two doses, acetaminophen 1000 mg was superior to acetaminophen 500 mg, and the efficacy of codeine 60 mg corresponded approximately to acetaminophen 500 mg.
Two randomized, double-blind studies (unpublished) evaluated the onset of analgesia using acetaminophen 1000 mg, naproxen sodium 220 mg and 440 mg, and placebo in patients who experienced moderate to severe postoperative dental pain. The first study found that all active treatments were more effective than placebo, and no difference for onset of pain relief between the active treatments was observed. The second study demonstrated that all active treatments had shorter time to onset of pain relief and were more effective than placebo.
Postpartum patients receiving a single 600-mg dose of acetaminophen reported a degree of relief greater than with either salicylamide or placebo and equivalent to the same dose of aspirin.71 Kantor and associates72 compared the effects of single doses of acetaminophen 600 mg and aspirin 600 mg or 1200 mg in postpartum patients. The three active treatments were significantly superior to placebo. In a double-blind evaluation comparing acetaminophen, propoxyphene, propoxyphene/acetamino-phen combination, and placebo, acetaminophen alone was comparable to the propoxyphene combination and superior to both propoxyphene alone and placebo.73 The analgesic efficacies of acetaminophen 650 mg, ibuprofen 200 mg, and placebo were evaluated in a randomized, double-blind study (unpublished) involving hospitalized postpartum patients with moderate to severe pain due to episiotomies. Both active treatments were superior to placebo, whereas ibuprofen was significantly better than acetaminophen.
McQuay and colleagues74,75 performed two studies comparing the analgesic equivalence and efficacy of varying doses of ketorolac, bromfenac, and acetaminophen in patients who had elective orthopedic surgery. In the first study, patients were treated with placebo plus one of the following: acetaminophen 500 mg, acetaminophen 1000 mg, ketorolac 5 mg, ketorolac 10 mg, or ketorolac 20 mg. Acetaminophen 1000 mg was significantly superior to acetaminophen 500 mg. Ketorolac 20 mg was superior to acetaminophen 500 mg and ketorolac 5 mg and 10 mg but was not superior to acetaminophen 1000 mg.75 In the second study, patients were randomized to receive placebo, acetaminophen 1000 mg, bromfenac 5 mg, bromfenac 10 mg, or bromfenac 25 mg. In terms of analgesic efficacy, bromfenac 10 mg was similar to acetaminophen 1000 mg.74
A randomized crossover study (unpublished) in primary dysmenorrhea compared the effect of acetaminophen 1000 mg four times daily, ibuprofen 400 mg three times daily, and placebo in patients with a history of recurrent moderate to severe dysmenorrhea. The two active drugs were comparable in the treatment of primary symptoms of dysmenorrhea, and both were superior to placebo.
Post-Immunization Muscle Aches and Pain
Aoki and associates76 evaluated the effect of acetaminophen on the incidence of adverse effects and immunogenicity of whole-virus influenza vaccine in healthcare workers. Hospital personnel volunteers were randomly assigned to acetaminophen 325 mg, acetaminophen 650 mg, or placebo. Capsules were taken at the time of the vaccination, and 4, 8, and 12 hours after vaccination. Acetaminophen 650 mg significantly reduced the incidence of sore arm and nausea without affecting antibody response.
Wallenstein and Houde77 found 600 mg of acetaminophen or aspirin to be approximately equivalent and significantly superior to salicylamide and placebo for pain relief in patients with cancer. Moertel and colleagues78 compared acetaminophen 650 mg, codeine 65 mg, aspirin 650 mg, pentazocine 50 mg, propoxyphene 65 mg, and ethoheptazine 75 mg in the treatment of cancer pain. On the basis of mean pain relief scores, neither propoxyphene nor ethoheptazine was statistically superior to placebo. Acetaminophen was superior to placebo and comparable to codeine, aspirin, and pentazocine for pain relief.
Acute Toxicity (Multiple Animal Models)
See Table 5.
Subacute Toxicity (Rats)
Oral doses of up to 1000 mg/kg/d or intramuscular doses of up to 100 mg/kg/d were given to rats for 13 days or 30 days, respectively. No drug-related changes were seen in mortality rate or necropsy findings compared with controls.
Subacute Toxicity (Dogs)
After acetaminophen (20 and 63 mg/kg/d) was given intramuscularly for 4 weeks to dogs, mortality rate, laboratory determinations, and gross necropsy observations were not significantly different from control values. Slight thyroid hyperplasia was seen on histopathologic examinations in the six high-dose dogs, slight renal tubular cell cloudy swelling was noted in three high-dose and one low-dose dog, and slight liver glycogen depletion was found in one control, three high-dose, and two low-dose animals.156
Chronic Toxicity (Rats)
Acetaminophen, 200 mg/kg/d, given to rats once a day by gavage for 28 weeks produced no changes in weight gain, gross pathology, or histologic findings in liver, kidney, heart, or lungs.157 Acetaminophen incorporated into the diet of rats for 100 days showed that the minimum dose that caused death in all rats was 1060 mg/kg/d, the dose that caused death in 50% of rats was 765 mg/kg/d, and the maximum dose that caused no deaths was 413 mg/kg/d. At or near the LD50 (100 days), histologic findings included areas of hepatic necrosis, some renal tubular degeneration, and testicular atrophy.158
TABLE 5. Acute toxicity (LD50 mg/kg) of acetaminophen
|Rat (1 day old)||NT||NT||> 600, < 700|
|Hamster||630-770||> 300, ≤ 548||NT|
|NT= not tested.|
Acute Nephrotoxicity (Rats)
Renal tubular lesions were observed in rats given single doses of acetaminophen in the lethal range of 2000 to 7000 mg/kg, and similar lesions were found in rats given 500 to 4000 mg/kg daily for up to 100 days. Attempts to produce renal damage with single nonlethal doses of acetaminophen have been unsuccessful.159
Chronic Nephrotoxicity (Rats)
In studies using rats, rabbits, and dogs, 50 to 400 mg/kg/d of acetaminophen for 13 to 40 weeks failed to produce any significant renal abnormalities, with no evidence of interstitial nephritis or papillary necrosis.159
Renal lesions have occurred in rats given 300 mg/kg/d for periods of up to 32 weeks in the presence of experimentally induced renal infection, whereas the same dose of acetaminophen failed to cause renal lesions in rats without pyelonephritis.160
* The American College of Rheumatology is an independent professional, medical, and scientific society that does not guarantee, warrant, or endorse any commercial product or service.
2. Flower RJ, Moncada S, Vane JR. Analgesic-antipyretics and anti-inflammatory agents; drugs employed in the treatment of gout. In: Gilman AG, Goodman LS, Gilman A, eds. The Pharmacologic Basis of Therapeutics. 7th ed. Elmsford, NY: Pergamon Press, Inc; 1985:692-695.
3. Guzman F, Braun C, Lim RKS, Potter GD, Rodgers DW. Narcotic and non-narcotic analgesics which block visceral pain evoked by intra-arterial injection of bradykinin and other analgesic agents. Arch Intern Pharmacodyn Ther. 1964;149:571-588.
4. Lim RKS, Guzman F, Rogers DW, et al. Site of action of narcotic and non-narcotic analgesics determined by blocking bradykinin-evoked visceral pain. Arch Intern Pharmacodyn. 1964;152:25-58.
5. Bjorkman R, Hallman KM, Hedner J, Hedner T, Henning M. Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. Pain. 1994;57:259-264.
6. Ameer B, Greenblatt DJ. Acetaminophen. Ann Intern Med. 1977;87:202-209.
7. Atkins E, Bodel P. Fever. In: Grant L, Mucluskey RT, eds. The Inflammatory Process. 5th ed. New York, NY: Academic Press; 1974;1:467-514.
8. Koch-Weser J. Drug therapy: acetaminophen. N Engl J Med. 1976;295:1297-1300.
9. Milton AS. Modern views on the pathogenesis of fever and the mode of action of antipyretic drugs. J Pharm Pharmacol. 1976;28(suppl 4):393-399.
10. Clark WG, Holdeman M, Lipton JM. Analysis of the antipyretic action of a-melanocyte-stimulating hormone in rabbits. J Physiol. 1985;359:459-465.
11. Wilkinson MF, Kasting NW. Vasopressin release within the ventral septal area of the rat brain during drug-induced antipyresis. Am J Physiol. 1993;264:R1133-R1138.
12. Wilkinson MF, Kasting NW. Central vasopressin V1-blockade prevents salicylate but not acetaminophen antipyresis. J Appl Physiol. 1990;68:1793-1798.
13. Feldberg W, Gupta KP, Milton AS, Wendlandt S. Effect of bacterial pyrogen and antipyretics on prostaglandin activity in cerebrospinal fluid of unanaesthetized cats. Br J Pharmacol. 1972;46:550P-551P.
14. Flower RJ, Vane JR. Inhibition of prostaglandin synthetase in brain explains the antipyretic activity of paracetamol (4-acetamidophenol). Nature. 1972;240:410-411.
15. McGilveray IJ, Mattok GL, Fooks JR, Jordan N, Cook D. Acetaminophen II: a comparison of the physiological availabilities of different commercial dosage forms. Can J Pharmaceut Sci. 1971;6:38-42.
16. Temple AR, Mrazik TJ. More on extended-release acetaminophen (letter). N Engl J Med. 1995;333:1508-1509.
17. Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Goodman Gilman A, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:1712.
18. Levy G. Comparative pharmacokinetics of aspirin and acetaminophen. Arch Intern Med. 1981;141:279-281.
19. Milligan TP, Morris HC, Hammond PM, Price CP. Studies on paracetamol binding to serum proteins. Ann Clin Biochem. 1994;31:492-496.
20. Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet. 1982;7:93-107.
21. Bannwarth B, Netter P, Lapicque F, et al. Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of propacetamol. Br J Clin Pharmacol. 1992;34:79-81.
22. Moreau X, Le Quay L, Granry JC, Boishardy N, Delhumeau A. Pharmacokinetics of acetaminophen in the cerebrospinal fluid in the elderly. Therapie. 1993;48:393-396.
23. Levy G, Garrettson LK, Soda DM. Evidence of placental transfer of acetaminophen (letter). Pediatrics. 1975;55:895.
24. Naga Rani MA, Joseph T, Narayanan R. Placental transfer of paracetamol. J Indian Med Assoc. 1989; 87:182-183.
25. Rollins DE, von Bahr C, Glaumann H, Moldeus P, Rane A. Acetaminophen: potentially toxic metabolite formed by human fetal and adult liver microsomes and isolated fetal liver cells. Science. 1979;205:1414-1416.
26. Berlin CM Jr, Yaffe SJ, Ragni M. Disposition of acetaminophen in milk, saliva, and plasma of lactating women. Pediatr Pharmacol. 1980;1:135-141.
27. Bitzen PO, Gustafsson B, Jostell KG, Melander A, Wahlin-Boll E. Excretion of paracetamol in human breast milk. Eur J Clin Pharmacol. 1981;20:123-125.
28. Notarianni LJ, Oldham HG, Bennett PN. Passage of paracetamol into breast milk and its subsequent metabolism by the neonate. Br J Clin Pharmacol. 1987;24:63-67.
29. Mitchell JR, Thorgeirsson SS, Potter WZ, Jollow DJ, Keiser H. Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther. 1974;16:676-684.
30. Patten CJ, Thomas PE, Guy RL, et al. Cytochrome P450 enzymes involved in acetaminophen activation by rat and human liver microsomes and their kinetics. Chem Res Toxicol. 1993;6:511-518.
31. Raucy JL, Lasker JM, Lieber CS, Black M. Acetaminophen activation by human liver cytochrome P450IIE1 and P450IA2. Arch Biochem Biophys. 1989;271:270-283.
32. Thummel KE, Lee CA, Kunze KL, Nelson SD, Slattery JT. Oxidation of acetaminophen to N-acetyl-p-aminobenzoquinone imine by human CYP3A4. Biochem Pharmacol. 1993;45:1563-1569.
33. Prescott L. Paracetamol: A Critical Bibliographic Review. London: Taylor and Francis, Ltd; 1996.
34. Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther. 1976;19:284-294.
35. Rawlins MD, Henderson DB, Hijab AR. Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration. Eur J Clin Pharmacol. 1977;11:283-286.
36. Lee HS, Ti TY, Koh YK, Prescott LF. Paracetamol elimination in Chinese and Indians in Singapore. Eur J Clin Pharmacol. 1992;43:81-84.
37. Miners JO, Osborne NJ, Tonkin AL, Birkett DJ. Perturbation of paracetamol urinary metabolic ratios by urine flow rate. Br J Clin Pharmacol. 1992;34: 359-362.
38. Miners JO, Atwood J, Birkett DJ. Influence of sex and oral contraceptive steroids on paracetamol metabolism. Br J Clin Pharmacol. 1983;16:503-509.
39. Slattery JT, McRorie TI, Reynolds R, Kalhorn TF, Kharasch ED, Eddy AC. Lack of effect of cimetidine on acetaminophen disposition in humans. Clin Pharmacol Ther. 1989;46:591-597.
40. Veronese ME, McLean S. Metabolism of paracetamol and phenacetin in relation of debrisoquine oxidation phenotype. Eur J Clin Pharmcol. 1991;40:547-552.
41. Andrews RS, Bond CC, Burnett J, Saunders A, Watson K. Isolation and identification of paracetamol metabolites. J Int Med Res. 1976;4(suppl 4):34-39.
42. Klutch A, Levin W, Chang RL, Vane F, Conney AH. Formation of a thiomethyl metabolite of phenacetin and acetaminophen in dogs and man. Clin Pharmacol Ther. 1978;24:287-293.
43. Mrochek JE, Katz S, Christie WH, Dinsmore SR. Acetaminophen metabolism in man, as determined by high-resolution liquid chromatography. Clin Chem. 1974;20:1086-1096.
44. Critchley JA, Nimmo GR, Gregson CA, Woolhouse NM, Prescott LF. Intersubject and ethnic differences in paracetamol metabolism. Br J Clin Pharmacol. 1986;22:649-657.
45. Esteban A, Calvo R, Perez-Mateo M. Paracetamol metabolism in two ethnically different Spanish populations. Eur J Drug Metab Pharmacokinet. 1996;21:233-239.
46. Osborne NJ, Tonkin AL, Miners JO. Interethnic differences in drug glucuronidation: a comparison of paracetamol metabolism in Caucasians and Chinese. Br J Clin Pharmacol. 1991;32:765-767.
47. Temple AR. Pediatric dosing of acetaminophen. Pediatr Pharmacol. 1983;3:321-327.
48. Amadio P, Cummings DM. Evaluation of acetaminophen in the management of osteoarthritis of the knee. Curr Ther Res. 1983;34:59-66.
49. Bradley J D, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med. 1991;325: 87-91.
50. Williams HJ, Ward JR, Egger MJ, et al. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis Rheum. 1993;36:1196-1206.
51. Simila S, Keinanen S, Kouvalainen K. Oral antipyretic therapy: evaluation of benorylate, an ester of acetyl-salicylic acid and paracetamol. Eur J Pediatr. 1975;121:15-20.
52. Steele RW, Young FH, Bass JW, Shirkey HC. Oral antipyretic therapy: evaluation of aspirin-acetaminophen combination. Am J Dis Child. 1972;123:204-206.
53. Agbolosu NB, Cuevas LE, Milligan P, Broadhead RL, Brewster D, Graham SM. Efficacy of tepid sponging versus paracetamol in reducing temperature in febrile children. Ann Trop Pediatr. 1997;17:283-288.
54. Friedman AD, Barton LL. Efficacy of sponging versus acetaminophen for reduction of fever. Pediatr Emerg Care. 1990;6:6-7.
55. Hunter J. Study of antipyretic therapy in current use. Arch Dis Child. 1973;48:313-315.
56. Kinmonth AL, Fulton Y, Campbell MJ. Management of feverish children at home. BMJ. 1992;305:1134-1136.
57. Eden AN, Kaufman A. Clinical comparison of three antipyretic agents. Am J Dis Child. 1967;114:284-287.
58. Tarlin L, Landrigan P, Babineau R, Alpert JJ. A comparison of the antipyretic effect of acetaminophen and aspirin: another approach to poison prevention. Am J Dis Child. 1972;124:880-882.
59. Kauffman RE, Sawyer LA, Scheinbaum ML. Antipyretic efficacy of ibuprofen vs acetaminophen. Am J Dis Child. 1992;146:622-625.
60. Walson PD, Galletta G, Chomilo F, Braden NJ, Alexander Sawyer L, Scheinbaum ML. Comparison of multidose ibuprofen and acetaminophen therapy in febrile children. Am J Dis Child. 1992;146:626-632.
61. Walson PD, Galletta G, Braden NJ, Alexander L. Ibuprofen, acetaminphen, and placebo treatment of febrile children. Clin Pharmacol Ther. 1989;46:9-17.
62. Wilson JT, Don Brown R, Kearns GL, et al. Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children. J Pediatr. 1991;119:803-811.
63. Wilson JT, Don Brown R, Kearns GL, et al. Comparative efficacy of ibuprofen and acetaminophen in febrile children. Eur J Pharmacol. 1990;183:2277-2278.
64. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis, part I: osteoarthritis of the hip; part II: osteoarthritis of the knee. Arthritis Rheum. 1995;38:1535-1546.
65. Skoglund LA, Petterson N. Effects of acetaminophen after bilateral oral surgery: double dose twice daily versus standard dose four times daily. Pharmacotherapy. 1991;11:370-375.
66. Skoglund LA, Skjelbred P, Fyllingen G. Analgesic efficacy of acetaminophen 1000 mg, acetaminophen 2000 mg, and the combination of acetaminophen 1000 mg and codeine phosphate 60 mg versus placebo in acute postoperative pain. Pharmacotherapy. 1991;11:364-369.
67. Cooper SA, Schachtel BP, Goldman E, Gelb S, Cohn P. Ibuprofen and acetaminophen in the relief of acute pain: a randomized, double-blind, placebo-controlled study. J Clin Pharmacol. 1989;29:1026-1030.
68. Mehlisch DR, Sollecito WA, Helfrick JF, et al. Multicenter clinical trial of ibuprofen and acetaminophen in the treatment of postoperative dental pain. J Am Dent Assoc. 1990;121:257-263.
69. Rodrigo C, Chau M, Rosenquist J. A comparison of paracetamol and diflunisal for pain control following 3rd molar surgery. Int J Oral Maxillofac Surg. 1989;18:130-132.
70. Quiding H, Oikarinen V, Sane J, Sjoblad AM. Analgesic efficacy after single and repeated doses of codeine and acetaminophen. J Clin Pharmacol. 1984;24:27-34.
71. Lasagna L, Davis M, Pearson JW. A comparison of acetophenetidin and acetaminophen, I: analgesic effects in postpartum patients. J Pharmacol Exp Ther. 1967;155:296-300.
72. Kantor TG, Meisner M, Laska E, Sunshine A. A computer program for the clinical study of analgesic compounds (abstract). Fed Proc. 1964;23:176.
73. Hopkinson JH III, Bartlett FH Jr, Steffens AO, McGlumphy TH, Macht EL, Smith L. Acetaminophen versus propoxyphene hydrochloride for relief of pain in episiotomy patients. J Clin Pharmacol. 1973;13:251-263.
74. McQuay HJ, Carroll D, Frankland T, Harvey M, Moore A. Bromfenac, acetaminophen, and placebo in orthopedic postoperative pain. Clin Pharmacol Ther. 1990;47:760-766.
75. McQuay HJ, Poppleton P, Carroll D, Summerfield RJ, Bullingham RE, Moore RA. Ketorolac and acetaminophen for orthopedic postoperative pain. Clin Pharmacol Ther. 1986;39:89-93.
76. Aoki FY, Yassi A, Cheang M, et al. Effects of acetaminophen on adverse effects of influenza vaccination in health care workers. CMAJ. 1993;149:1425-1430.
77. Wallenstein SL, Houde RW. Clinical comparison of analgesic effectiveness of N-acetyl-aminophenol, salicylamide, and aspirin (abstract). Fed Proc. 1954;13:414.
78. Moertel CG, Ahmann DL, Taylor WF, Schwartau N. A comparative evaluation of marketed analgesic drugs. N Engl J Med. 1972;286:813-815.
79. Schachtel BP, Fillingim JM, Thoden WR, Lane AC, Baybutt RI. Sore throat pain in the evaluation of mild analgesics. Clin Pharmacol Ther. 1988;44:704-711.
80. Reuter SH, Montgomery WW. Aspirin versus acetaminophen after tonsillectomy. Arch Otolaryngol. 1964;80:214-217.
81. Anderson B, Kanagasundarum S, Woollard G. Analgesic efficacy of paracetamol in children using tonsillectomy as a pain model. Anaesth Intens Care. 1996;24:669-673.
156. Toxicological Research Report. Safety evaluation of Tylenol® (acetaminophen, McN-R-51) by repeated intramuscular administration to dogs for 4 weeks. McNeil Laboratories, Inc. November 21, 1963.
157. Thomas BH, Nera EA, Zeitz W. Failure to observe pathology in the rat following chronic dosing with acetaminophen and acetylsalicylic acid. Res Comm Chem Pathol Pharmacol. 1977;17:663-678.
158. Boyd EM, Hogan SE. The chronic oral toxicity of paracetamol at the range of the LD50 (100 days) in albino rats. Can J Physiol Pharmacol. 1968;46: 239-245.
159. Prescott LF. Analgesic nephropathy: a reassessment of the role of phenacetin and other analgesics. Drugs. 1982;23:75-149.
160. Furman KI, Kundig H, Lewin JR. Experimental paracetamol nephropathy and pyelonephritis in rats. Clin Nephrol. 1981;16:271-275.
Last reviewed on RxList: 11/7/2007
This monograph has been modified to include the generic and brand name in many instances.
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