Hepatic Effects

The most serious complication associated with acetaminophen use is hepatotoxicity (liver damage) as a result of overdose. In the healthy adult, a maximum daily dose below 4 gm is only rarely associated with liver toxicity (American Pain Society [APS], 2003; Bolesta, Haber, 2002; Laine, White, Rostom, et al., 2008; Rumack, 2002; Watkins, Kaplowitz, Slattery, et al., 2006). However, repeated doses exceeding this amount can result in hepatotoxicity (Daly, O’Malley, Heard, et al., 2004; United States Food and Drug Administration [U.S. FDA], 2009), and very large single doses can lead to fulminant hepatic failure.

Acetaminophen should be administered cautiously, at lower maximum doses, or not at all in situations that pose an increased risk of acetaminophen-associated hepatic injury. Factors that increase this risk include preexisting liver disease, the concurrent use of potentially hepatotoxic medications, fasting or poor nutrition, and regular consumption of alcohol (AGS, 2009; APS, 2003; Burke, Smyth, Fitzgerald, 2006; Larson, Polson, Fontana, et al., 2005; Miaskowski, Cleary, Burney, et al., 2005). Although some research shows that 4 gm per day can be safely taken in individuals who regularly drink alcohol (Graham, Scott, Day, 2005; Kuffner, Dart, 2001), the APS recommends no more than 2.5 gm per day in individuals who consume more than 2 ounces of alcohol daily because of the elevated risk of hepatotoxicity (Simon, Lipman, Caudill-Slosberg, et al., 2002). The U.S. FDA requires acetaminophen product labeling to warn consumers of the increased risk of liver damage when acetaminophen is taken by those who consume three or more alcoholic drinks per day (U.S. FDA, 2009). Acetaminophen at doses less than the maximum recommended amount may be problematic with alcohol intake as well. One study showed 65% of the subjects with acute liver failure who reported taking less than 4 gm per day were alcohol abusers (Larson, Polson, Fontana, et al., 2005). The American Geriatrics Society (AGS) lists chronic alcohol abuse/dependence as a relative contraindication to using acetaminophen (AGS, 2009).

Most experts recommend a reduction in daily dose in individuals who are at high risk for hepatotoxicity (Burke, Smyth, FitzGerald, 2006). For example, the AGS recommends a 50% to 75% reduction in dose in older individuals with hepatic insufficiency (AGS, 2009). Recommendations vary, however. Some authors recommend avoiding acetaminophen entirely in patients with hepatic insufficiency (Bannwarth, Pehourcq, 2003), whereas others suggest that it should be used as the optimal analgesic for patients with stable chronic liver disease (Graham, Scott, Day, 2005). Liver function tests should be performed every 6 to 12 months in any individual at high risk for hepatotoxicity who is taking acetaminophen (Bannwarth, 2006; Miaskowski, Cleary, Burney, et al., 2005; Simon, Lipman, Caudill-Slosberg, et al., 2002) (see Chapter 7 for more on acetaminophen dosing).

Acetaminophen overdose is a common cause of liver failure. A 6-year prospective study of 662 patients with acute liver failure showed that 42% of the cases resulted from acetaminophen hepatotoxicity, and 48% of those were from unintentional acetaminophen overdose (Larson, Polson, Fontana, et al., 2005). A review of the United Network for Organ Sharing data revealed acetaminophen alone or in combination with other drugs accounted for 49% of the drug-related liver transplants performed in the United States between 1990 and 2002 (Russo, Galanko, Shrestha, et al., 2004).

A retrospective review of 1543 patients hospitalized for acetaminophen overdose revealed that 4.5% developed hepatotoxicity despite antidote treatment (n-acetylcysteine) in 38% (Myers, Shaheen, Li, et al., 2008) (see Chapter 10 for more on overdose treatment). While the occurrence of hepatotoxicity was low in this review, the patients who did develop it were 2.5 times more likely to be admitted to the intensive care unit (ICU) and 40 times more likely to die in the hospital than those without liver damage. This led researchers to conclude that the nature of most acetaminophen overdoses is relatively benign, but the clinical impact for those who do develop hepatotoxicity is significant. This review also reinforced the impact of known risk factors—34% were alcohol abusers, 13% overdosed accidentally, and 3% had underlying liver disease (Myers, Shaheen, Li, et al., 2008). A significant finding was that the 13% who accidentally overdosed represented 49% of the cases of hepatotoxicity in this study. Co-morbidities were common (82%) in the individuals who overdosed; in addition to liver disease and alcohol abuse, 55% suffered depression. Older age was also identified as a risk factor.

The wide availability of formulations that combine acetaminophen with other ingredients for the treatment of a variety of conditions, ranging from the common cold to pain, increases the chances of exceeding recommended daily doses (Myers, Shaheen, Li, et al., 2008). For example, one of the aforementioned studies (Larson, Polson, Fontana, et al., 2005) noted that, of the 48% who had acute liver failure following unintentional overdose, 38% had taken two or more acetaminophen products simultaneously and 63% had taken opioid-acetaminophen formulations.

The risk of unintentional overdose from acetaminophen mandates that patient teaching be done when prescribing an acetaminophen-containing drug and that this discussion describes safe maximum doses and the types of OTC analgesics and medications, such as cold remedies and sleep aids, that should be avoided (Bataller, 2007; Scharbert, Gebhardt, Sow, et al., 2007) (see Patient Medication Information Form III-4 on pp. 256-257; see Form III-5 on pp. 258-259 for aspirin). In 2009, the U.S. FDA required label changes for acetaminophen and products containing acetaminophen to reflect an increased risk of liver damage under certain circumstances (e.g., maximum daily dose is exceeded, daily intake of three or more alcoholic drinks, preexisting liver disease, concomitant use of other drugs containing acetaminophen) (U.S. FDA, 2009). In addition to product labeling changes, reformulation of acetaminophen-containing opioid analgesics has been proposed to reduce the rising incidence of this preventable form of liver injury (Fontana, 2008).

There may be racial or ethnic differences in the pharmacokinetics of acetaminophen and the development of hepatotoxicity following overdose. A small study comparing acetaminophen in Chinese (N = 11) and Caucasian (N = 9) subjects showed the Chinese more rapidly absorbed a single dose of acetaminophen and tended to produce reduced amounts of cysteine and mercapturic acid conjugates, compounds that may help protect against hepatotoxicity following acetaminophen overdose (Critchley, Critchley, Anderson, et al., 2005). Further research is needed to describe these and other sources of individual variation in the risks associated with this drug.

Renal Effects

The risk of chronic renal failure also has been linked to long-term acetaminophen use (Bannwarth, 2006) (see Chapter 8 for renal effects in the perioperative setting). The Nurses’ Health Study, established in 1976, utilized questionnaires to evaluate 121,700 female registered nurses for a wide variety of health-related conditions (Colditz, 1995). A cohort (N = 1697) of this study was evaluated later for the effect of acetaminophen, aspirin, or other NSAID use on renal function, as measured by glomerular filtration rate (GFR) (Curhan, Knight, Rosner, et al., 2004). High acetaminophen, but not NSAID or aspirin use, was associated with an increased risk of decline in renal function. Women who used more than 100 gm of acetaminophen over the 11-year collection period had a GFR decline of at least 30%.

Other epidemiologic studies also have shown an association between acetaminophen use and chronic renal failure. For example, a study of nearly 1000 individuals with newly diagnosed early-stage chronic renal failure and nearly 1000 individuals without renal failure observed that aspirin and acetaminophen were used regularly by 37% and 25%, respectively, of the patients with renal failure, and by 19% and 12%, respectively, of the control group (Fored, Ejerblad, Lindblad, et al., 2001). Regular use (twice weekly for 2 months) of either drug alone was associated with a 2.5 increase in risk of chronic renal failure, and the relative risk rose more with increasing cumulative lifetime doses of acetaminophen than aspirin.

None of these epidemiologic studies confirm causality. Although the renal disease may be directly related to long-term acetaminophen use, it is possible that renal insufficiency caused by other disorders leads to pain and self-medication with acetaminophen, or that both renal dysfunction and acetaminophen use are related to a third factor. It is prudent to consider chronic renal failure as a potential complication of this drug, but recognize the need for additional research to define the relationship better.

Although acetaminophen may cause kidney disease, it usually is preferred over NSAIDs as a treatment for mild to moderate pain in patients with preexisting renal insufficiency (Bannwarth, 2006; Bannwarth, Pehourcq, 2003). This conventional view has been justified by the perceived lack of effect on platelet aggregation (which may be overstated; see discussion later in the chapter) and the low incidence of GI adverse effects (Kurella, Bennett, Chertow, 2003; Launay-Vacher, Karie, Fau, et al., 2005). Dose adjustment also is not necessary in the presence of preexisting renal failure, as it is when acetaminophen is prescribed to those with liver disease.

Cardiovascular (CV) Effects

Although CV adverse effects may be increased by acetaminophen, studies of this phenomenon are minimal and the underlying mechanisms are unclear (Chan, Manson, Albert, et al., 2006). Phenacetin, the precursor to acetaminophen, is associated with increased CV morbidity and mortality (Chan, Manson, Albert, et al., 2006), and there are data suggesting a relationship between acetaminophen dose and CV risk. A prospective study that evaluated the incidence of nonfatal and fatal coronary heart disease, and nonfatal and fatal stroke in nearly 71,000 female NSAID or acetaminophen users found that the relative risk of these outcomes was 1.38 in women who regularly (22 days or more/month) consumed acetaminophen, compared with 1.44 in those with frequent use of NSAIDs (Chan, Manson, Albert, et al., 2006). A dose-dependent risk was evident with a relative risk of 1.86 and 1.68 for those who took 15 tablets or more/week of NSAIDs or acetaminophen, respectively, compared with those who took lower doses.

Acetaminophen use may also contribute to the incidence of hypertension. Curhan and colleagues conducted a prospective study of 80,020 women who participated in the Nurses’ Health Study (Colditz, 1995) and had no previous history of hypertension to examine the effect of acetaminophen, aspirin, or other NSAID use on BP (Curhan, Willett, Rosner, et al., 2002). Compared with nonusers, the relative risk of hypertension was 1.2 and 2.0 for those taking acetaminophen for 1 to 4 days/month and 22 days/month, respectively. This means that those taking acetaminophen 22 days/month were twice as likely to develop hypertension as those who did not use acetaminophen. Other analysis has yielded similar elevated risk (Dedier, Stampfer, Hankinson, et al., 2002). An analysis of younger (N = 3220) and older (N = 1903) age cohorts of the Nurses’ Health Study revealed a correlation between relative risk of hypertension and dose of acetaminophen (Forman, Stampfer, Curhan, 2005). Dose but not age was associated with increased risk in those who took more than 500 mg/day; relative risk was 1.99 and 1.93 for younger and older women, respectively.

A later study of analgesic use in 16,031 non- hypertensive male health care professionals had similar results (Forman, Rimm, Curhan, 2007). A review of detailed information about the use of acetaminophen, aspirin, and other NSAIDs by these men revealed a relative risk of 1.34 in those who took acetaminophen 6 to 7 days per week compared with those who used no acetaminophen. The relative risk was 1.38 for NSAIDs and 1.26 for aspirin.

In contrast, a large prospective cohort study of 8229 males without hypertension at the start of a 5.8 year (mean) follow-up period found that, compared with those who never used acetaminophen, NSAIDs, or aspirin, there was no significant increase in risk of subsequent hypertension in the men who took at least 2500 pills of any of the analgesics. A small to moderately increased risk cannot be excluded from observational studies (Kurth, Hennekens, Sturmer, et al., 2005), and all observational studies must be interpreted cautiously given the potential for recall and other sources of bias (Vardeny, Solomon, 2008).

Hematologic Effects and Anticoagulant Therapy

Acetaminophen has long been used as an analgesic in patients receiving anticoagulation therapy because it was thought to have no effect on platelet aggregation (Thijssen, Soute, Vervoort, et al., 2004). Nonetheless, there are conflicting observations, which together suggest that acetaminophen may in fact interfere with platelet aggregation and potentiate the anticoagulant effect of warfarin (Coumadin) (Gebauer, Nyfort-Hansen, Henschke, et al., 2003; Mahe, Bertrand Drouet, et al., 2006; Munsterhjelm, Munsterhjelm, Niemi, et al., 2005; Ornetti, Ciappuccini, Tavernier, et al., 2005; Parra, Beckey, Stevens, 2007; Thijssen, Soute, Vervoort, et al., 2004). If indeed this is a clinically relevant effect, it may be related to the weak inhibition of COX-1 produced by acetaminophen (Munsterhjelm, Munsterhjelm, Niemi, et al., 2005) and the production of metabolites that may interfere with the enzymes involved in vitamin K–dependent coagulation factor synthesis (Mahe, Bertrand, Drouet, et al., 2005, 2006; Thijssen, Soute, Vervoort, et al., 2004).

A small double-blind, crossover study of 13 healthy male volunteers with normal platelet function was conducted to evaluate the dose-dependent effect of acetaminophen on platelet function (Munsterhjelm, Munsterhjelm, Niemi, et al., 2005). Compared with those who received placebo, the men who received IV acetaminophen demonstrated a dose-dependent increase in concentration of arachidonic acid, which was thought to cause the anticoagulant effect seen in the volunteers. In addition, acetaminophen inhibited the release of thromboxane B₂, the stable metabolite of thromboxane A₂, released during platelet aggregation. This effect was also dose dependent. Another small (N = 11) double-blind, crossover study randomized patients to receive 14-day regimens of acetaminophen (4 gm) or placebo with a 14-day wash-out period between (Mahe, Bertrand, Drouet, et al., 2005). The International Normalized Ratio (INR), a measure of coagulation, was significantly elevated in patients who received acetaminophen compared with those who received placebo.

The effect of 2 to 4 gm/day of acetaminophen on patients receiving warfarin anticoagulation therapy was evaluated in a randomized, placebo-controlled trial of 36 adults at an anticoagulation clinic (Parra, Beckey, Stevens, 2007). The patients were receiving warfarin and had stable INRs at the start of the study. The study was terminated after 15 patients demonstrated a significant dose-dependent increase in INR. There was also a significant increase in mean serum alanine aminotransferase (ALT) level (liver function indicator) in the patients who received 4 g/day of acetaminophen compared with those who received placebo. Another randomized, placebo-controlled study (N = 20) showed similar results (Mahe, Bertrand, Drouet, et al., 2006). Again, patients were stabilized on warfarin anticoagulation therapy. The mean INR increased quickly and significantly within 1 week of acetaminophen (4 gm/day) use. There were also significant reductions in vitamin K–dependent clotting factors.

These studies support the view that acetaminophen can have clinically relevant hematologic effects. It also is true, however, that acetaminophen inhibition of thromboxane A₂ is less than that of the nonselective NSAIDs (Munsterhjelm, Niemi, Syrjala, et al., 2003), and studies have shown that surgical bleeding as a result of perioperative acetaminophen intake is low (Ashraf, Wong, Ronayne, et al., 2004; Munsterhjelm, Munsterhjelm, Niemi, et al., 2005) (see Chapter 8 for effect of perioperative nonopioid use on surgical site bleeding). It is probable that the risk of bleeding associated with acetaminophen use is low, but given the extant data, close monitoring of patients receiving acetaminophen and anticoagulation therapy is prudent (Mahe, Bertrand Drouet, et al., 2005, 2006; Ornetti, Ciappuccini, Tavernier, et al., 2005; Parra, Beckey, Stevens, 2007). In 2009, the U.S. FDA required label changes for acetaminophen to advise those who are taking warfarin to discuss the use of acetaminophen with a pharmacist or physician prior to taking acetaminophen (U.S. FDA, 2009).

Gastrointestinal (GI) Effects

The most common adult daily dose of acetaminophen is 1000 mg, a dose that is thought to produce less GI toxicity than most NSAIDs (Burke, Smyth, Fitzgerald, 2006). However, daily doses of more than 500 mg have been shown to diminish gastric mucosal protection (Rahme, Pettitt, LeLorier, 2002), and epidemiologic studies show doses of more than 2000 mg/24 h produce increased risk of severe upper GI adverse effects (Bannwarth, 2006). A study of analgesic overdose by patients with suicidal intent reported endoscopic gastric damage (lesions) from acute high-dose acetaminophen to be similar to that caused by acute high-dose NSAID ingestion (Soylu, Dolapcioglu, Dolay, et al., 2008). This is likely due, at least in part, to peripheral COX-1 inhibition (associated with poorer gastric safety). Indeed, acetaminophen has been shown to be more COX-1 selective than several NSAIDs, including naproxen (Naprosyn, Aleve), diclofenac (Voltaren), and ibuprofen (Advil, Motrin), but less than piroxicam (Feldene) and tolmetin (Tolectin) (Rahme, Pettitt, LeLorier, 2002).

A large cohort study of individuals aged 65 and older was undertaken to compare the rates of GI adverse events occurring with higher versus lower doses of acetaminophen (Rahme, Pettitt, LeLorier, 2002). Data from patients who had received a prescription for acetaminophen (N = 21,000) or a nonaspirin NSAID (N = 27,000) were examined. Unadjusted rates of hospitalization, ulcer, and dyspepsia were higher for patients taking acetaminophen compared with those taking NSAIDs, and the acetaminophen GI adverse events were dose related. After adjustment of risk susceptibility, patients receiving higher acetaminophen doses (more than 3250 mg/day) had higher rates of GI events compared with those receiving lower doses (650 mg or less/day).

Gastrointestinal (GI) Effects

The most common adverse effects of the NSAIDs involve the GI system. The associated clinical conditions are heterogeneous, and the most serious concern involves GI ulceration. Ulcers and their complications, including hemorrhage and perforation, can occur in both the upper and lower GI tract (Hayashi, Yamamoto, Kita, et al., 2005). These serious events may be difficult to detect and can be fatal (Simon, 2007).

NSAID-induced GI events are blamed for an estimated 100,000 hospitalizations and 16,500 deaths annually in the United States (Bombardier, Laine, Reicin, et al., 2000). Studies have demonstrated that the risk for serious GI complications is 3- to 5-fold higher in those who take NSAIDs than in those who do not (Wilcox, Allison, Benzuly, et al., 2006) and that gastric or duodenal ulceration may occur in 15% to 30% of patients receiving long-term therapy with NSAIDs classified as nonselective COX-1/COX-2 inhibitors (Bombardier, Laine, Reicin, et al., 2000; Cryer, 2004; Laine, 2001). A review of 361 patients with peptic ulcer bleeding revealed that one-half of the cases was associated with NSAID use (Ramsoekh, Van Leerdam, Rauws, et al., 2005). An autopsy study of 713 individuals revealed gastric and duodenum ulceration in 22% of nonselective NSAID users compared with 12% of NSAID nonusers; small bowel ulcers were found in 8.4% of nonselective NSAID users compared with 0.6% of NSAID nonusers (Simon, 2007).

The primary underlying mechanism of NSAID-induced ulceration is thought to be inhibition of COX-1, which leads to reduction in GI-protective prostaglandins (Burke, Smyth, Fitzgerald, 2006; Simon, Weaver, Graham, et al., 1999). This is a systemic effect and can occur regardless of the route of administration of the NSAID (Laine, 2001). This means that GI adverse effects resulting from prostaglandin inhibition are possible when NSAIDs are taken orally, rectally, or parenterally. Systemic effects may be compounded by local processes produced by direct contact between GI mucosa and the drug. With the exception of nabumetone (Relafen), all of the nonselective NSAIDs are highly lipophilic and can easily penetrate the gastric mucosal barrier, which is a hydrophobic mucous layer along the stomach lining (Simon, 2007). This penetration is thought to result in oxidative uncoupling of cellular metabolism, producing cell death and localized tissue injury (Simon, 2007).

NSAID-induced adverse GI effects manifest as distressing symptoms alone, asymptomatic ulceration, or the more serious complications of GI bleeding, perforation, or obstruction (Cryer, 2004; Laine, 2001). Even though dyspepsia and other upper GI symptoms are commonly associated with the use of NSAIDs and often a reason for discontinuing NSAID therapy (Goldstein, Eisen, Burke, et al., 2002), these symptoms do not appear to predict the development of a more serious GI event in patients with no or low GI risk (Laine, 2001; Lanas, Bajador, Serrano, et al., 2000; Mellemkjaer, Biot, Sorensen, 2002; Simon, Fox, 2005). However, endoscopic evaluation is recommended in patients with high GI risk who experience significant NSAID treatment-induced dyspepsia (Chan, Hung, Suen, et al., 2004).

NSAID-induced adverse effects are related to the dose and duration of treatment. The higher the NSAID dose and the longer the duration of NSAID use, the higher the risk of cumulative GI toxicity (Chan, Graham, 2004). This cumulative toxicity also includes a period of relatively higher risk at the start of treatment (Wilcox, Allison, Benzuly, et al., 2006). Serious complications are most frequent during the first 3 months of NSAID administration (Gabriel, Jaakkimainen, Bombardier, 1991), and there is an 8% incidence of ulcer development within 1 week of regular NSAID use (Laine, 2001).