Continuing Education Activity

Many diseases and conditions list pain as a component of their presentation; as a result, pain management is of great importance to clinicians and patients alike. Acetaminophen (APAP - also known as paracetamol in many countries) is a non-opioid analgesic and antipyretic agent used to treat pain and fever. It is used as a single agent for mild to moderate pain and combined with an opioid analgesic for severe pain. This activity outlines the use, dosing, indications, contraindications, toxicity, and toxicity management of acetaminophen and highlights the role of the interprofessional team in caring for patients who take acetaminophen.

Objectives:

• Identify the indications for acetaminophen use.
• Describe the potential toxicity of acetaminophen.
• Explain how to monitor for acetaminophen toxicity.
• Review interprofessional team strategies for improving care coordination so that acetaminophen therapy is optimized as a useful tool to improve patient outcomes in pain management.

Indications

Acetaminophen (APAP) is a non-opioid analgesic and antipyretic agent used to treat pain and fever. Clinicians can use it for their patients as a single agent for mild to moderate pain and in combination with an opioid analgesic for severe pain. 

Mechanism of Action

Acetaminophen, also called N-acetyl para-aminophenol (APAP) or paracetamol, is one of the most widely used over-the-counter analgesic and antipyretic agents.[1] Although its exact mechanism of action remains unclear, it is historically categorized along with NSAIDs because it inhibits the cyclooxygenase (COX) pathways.[2][3] Like NSAIDs, acetaminophen has analgesic and antipyretic properties. However, studies have shown that acetaminophen lacks peripheral anti-inflammatory properties. Acetaminophen may inhibit the COX pathway in the central nervous system but not peripheral tissues. Additionally, acetaminophen does not appear to bind to the active site of either the COX-1 or COX-2 enzyme; instead, it reduces the activity of COX by a different mechanism. It also has been theorized that acetaminophen inhibits a splice variant of COX-1, also called COX-3, but this has not been confirmed in humans.[4]

Regardless, the reduction of the COX pathway activity by acetaminophen is thought to inhibit the synthesis of prostaglandins in the central nervous system, leading to its analgesic and antipyretic effects. The analgesic properties may be due to a stimulating effect on the descending serotonergic pathways in the central nervous system (CNS). Other studies have suggested that acetaminophen or one of its metabolites, e.g., AM 404, also can activate the cannabinoid system e.g., by inhibiting the uptake or degradation of anandamide and 2-arachidonoylglyerol, contributing to its analgesic action.    

Administration

Acetaminophen can be administered orally, rectally, or intravenously (IV).[5]

• Oral:  Acetaminophen is available as a tablet, capsule, syrup, oral solution, or suspension. 
• Rectal: Acetaminophen is available as a rectal suppository for both adult and pediatric patient populations.
• Intravenous: Acetaminophen also comes as an IV infusion for administration.

Tompkins D. et al. reviewed the literature on the efficacy of intravenous (IV) acetaminophen in postoperative pain control.[6] The investigators found a lack of evidence for the efficacy of IV acetaminophen when comparing oral/rectal acetaminophen, opioid analgesics, NSAIDs, or placebo in abdominal, gynecologic, genitourinary, orthopedic, neurosurgical, cardiac, renal surgeries. The investigators conclude that IV acetaminophen has limited clinical benefit versus oral or rectal administration.

Adverse Effects

 Adverse effects of acetaminophen administered orally or rectally may include the following:

• Skin rash, hypersensitivity reactions
• Nephrotoxicity (elevations in BUN, creatinine)
• Hematological: anemia, leukopenia, neutropenia, pancytopenia
• Metabolic and electrolyte
• Decreased serum bicarbonate
• Decreased concentrations of sodium and calcium
• Hyperammonemia
• Hyperchloremia
• Hyperuricemia
• Increased serum glucose
• Increased bilirubin and alkaline phosphatase

Additional adverse effects of acetaminophen administered intravenously include nausea, vomiting, constipation, pruritus, and abdominal pain.

Rare but serious adverse effects include hypersensitivity, anaphylactic reactions, and serious and even fatal skin reactions. These include toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and Stevens-Johnson syndrome. 

FDA Boxed Warnings

Hepatotoxicity

Acetaminophen use has been linked to liver failure and sometimes has led to liver transplants or death. The hepatotoxicity occurring with acetaminophen use typically correlates with high doses of acetaminophen that exceed the recommended maximum dose.[7][8] This effect may involve the intake of more than one drug product that contains acetaminophen as an ingredient. Liver damage also has been seen in patients with chronic dosing of acetaminophen.

Dosing Errors

There is also an FDA boxed warning to avoid dosing errors, particularly when administering acetaminophen to pediatric patients, as well as making sure that the total daily dose of acetaminophen does not exceed the recommended maximum when taking into account all medications that contain acetaminophen.  

Although these effects, warnings, and associations have been documented, acetaminophen remains a safe and effective medication when used correctly. The current manufacturer dose recommendation is limited to between 3 and 3.25 grams in 24 hours, depending on the formulation. However, toxicity is rare at less than 150 mg/kg for an adult or 200 mg/kg for a child. 

Contraindications

Contraindications to using acetaminophen include hypersensitivity to acetaminophen, severe hepatic impairment, or severe active hepatic disease. However, there is a general debate among experts as to whether hepatic impairment is truly a limiting factor, as it would likely be associated with decreased production of the toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). 

Monitoring

Patients treated with acetaminophen should have monitoring for desired clinical effects, such as pain or fever relief. Serum concentrations are unnecessary when appropriately dosed. In overdose settings, laboratory evaluation is necessary. In acute overdoses in which ingestion occurs over less than eight hours, a serum APAP concentration should be assessed and plotted on the Rumack-Matthew nomogram, with the time course starting at the onset of ingestion, to determine toxicity and need for treatment. Nonacute ingestions require an assessment of acetaminophen concentration and transaminases, and treatment should occur. 

Additionally, caution is necessary for patients with renal or hepatic impairment or patients with alcoholic liver disease, glucose 6-phosphate dehydrogenase deficiency, or severe hypovolemia. However, there is evidence that acetaminophen may be safe to use in the setting of alcoholic liver disease.[9]

Acetaminophen can cross the placental barrier, but there is no evidence of increased teratogenic effects due to using normal doses of acetaminophen during pregnancy.[10] Acetaminophen also is excreted into breast milk, but there have not been many observations of adverse reactions in nursing infants.

Pregnant women should exercise caution when using acetaminophen early in pregnancy because of increasing evidence that in utero acetaminophen exposure to the fetus might increase the risk of neurological, reproductive, and urogenital disorders.[11] Alemany S. et al. studied prenatal and postnatal acetaminophen exposure in relation to Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD).[12] Acetaminophen exposure was assessed in 73,881 mother-child pairs using questionnaires or interviews. Children ages 4 to 12 with ASC or ADHD symptoms were evaluated using well-documented instruments. Children who were prenatally exposed to acetaminophen exposed had an increased risk of ASC (19 %) or ADHD (21%), borderline or clinical symptoms. However, postnatal acetaminophen exposure was not associated with ASC or ADHD symptoms.

MacIntyre I. et al. conducted a double-blind, placebo-controlled, crossover clinical trial on the effects of oral acetaminophen on daytime systolic blood pressure.[13] One hundred and ten subjects were randomized to receive 1 gram of acetaminophen four times a day or a placebo for two weeks, followed by a two-week washout period followed by receiving the alternative treatment. Daytime systolic blood pressure was measured in subjects who received acetaminophen or placebo. The investigators found a 5 mmHg increase in daytime systolic blood pressure in the subjects who received a daily dose of 4 g of acetaminophen. The investigators conclude that high-dose acetaminophen use in hypertensive patients could increase their cardiovascular disease risk.

Toxicity

Acetaminophen is responsible for an estimated 500 deaths and 50000 emergency department visits in the United States annually.[14] It is the most common drug-related cause of acute liver failure. The mechanism of hepatic injury is due to the drug metabolism properties of acetaminophen.[15] Following therapeutic concentrations of oral acetaminophen, 60% to 90% of the drug gets metabolized in the liver to glucuronic acid- and sulfate-conjugate metabolites. A smaller fraction (approximately 5% to 15%) undergoes metabolism by the cytochrome P450 system (CYP450). Metabolism primarily via CYP2E1 results in the formation of the toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI). 

Normally, NAPQI is neutralized by glutathione to nontoxic metabolites. However, with excessive doses of acetaminophen, the normal phase II drug metabolism pathways become depleted, and the CYP450 pathway metabolizes a higher portion of the acetaminophen taken, resulting in high concentrations of NAPQI formation, and the limited glutathione stores can become depleted. Without glutathione, NAPQI concentrations build up, and NAPQI, as a reactive intermediate, can react with cellular macromolecules, proteins, lipids, and nucleic acids. This phenomenon can lead to centrilobular (Zone 3) hepatic injury and hepatocellular death. There can also be nephrotoxicity.

The only approved antidote for acetaminophen overdose and toxicity is N-acetylcysteine (NAC).[16] NAC is a precursor to glutathione synthesis and helps restore the intracellular stores of glutathione to neutralize the NAPQI compound, and it can inactivate NAPQI directly. N-acetyl cysteine can be administered orally or by IV. IV N-acetyl cysteine is typically preferred because vomiting is common with acetaminophen overdose. It is effective when administered within the first few hours (up to 8 to 10 hours) of toxic acetaminophen ingestion. N-acetyl cysteine administration has a 20-hour IV or 72-hour oral protocol, and the clinician must monitor the AST/ALT during treatment.[17]

An important thing to remember is that most patients do not have symptoms in the first few hours of ingestion of toxic doses of acetaminophen and may only have abdominal pain and nausea as symptoms for the first 12 to 24 hours. These symptoms may dissipate between 24 and 72 hours, although AST/ALT concentrations may be abnormal. Patients who present more than 24 hours following ingestion of toxic doses of acetaminophen may have symptoms such as nausea, vomiting, jaundice, abdominal pain, and hypotension. These patients may require airway management, intravenous fluids, vasopressors, hemodialysis, or management of cerebral edema or other symptoms as they arise.

Enhancing Healthcare Team Outcomes

The most crucial aspect of acetaminophen toxicity is prevention. As part of the interprofessional healthcare team, clinicians (MDs, DOs, NPs, and PAs), nurses, and pharmacists. Pharmacists and nurses need to emphasize the maximum dose permitted daily. Patients also need to understand how to look for acetaminophen in various medications and calculate the dose they receive when they combine products. Pharmacists need to perform medication reconciliation to look for drug interactions and verify that there are not too many acetaminophen-containing drugs in the regimen. If there are concerns, the pharmacist should report them to the nurse and prescriber. All team members must document their findings and keep the entire team in the information loop regarding the patient's case.

With the recent changes in maximum daily dosing for acetaminophen, all interprofessional team members must be aware of the new guidelines and remain current should any new guidance come out.

If toxicity occurs or there is suspicion of toxicity, management also requires an interprofessional team of clinicians, nurses, and pharmacists. Specific protocols have been designed to direct the interprofessional team when patients present to emergency departments with acute acetaminophen toxicity. Emergency physicians, nurses, toxicologists, pharmacists, and psychiatrists developed one such protocol.[18] Dentists can also become involved when the overdose is secondary to dental procedures.[19] Notably, upon discharge, patients should be provided with clear instructions on APAP medication management, as outlined above. While acetaminophen has been available for many years and is generally safe, a coordinated interprofessional team effort is necessary to avoid avoidable toxicity by accounting for all sources of acetaminophen in the patient's medication profile. [Level 5]