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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.2015.01.024 588 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 JOE — Volume 41, Number 5, May 2015 Review Article 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). JOE — Volume 41, Number 5, May 2015 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 Acetaminophen Old Drug, New Issues 589 Review Article 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 590 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). JOE — Volume 41, Number 5, May 2015 Review Article 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. 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