Acetaminophen is one of the most commonly used over-the-counter (OTC) medications in the United States. It is strictly classified as a centrally acting analgesic and antipyretic agent, is a common treatment of mild to moderate pain, and is often a recommended first-line of analgesic therapy. Acetaminophen is sometimes combined with opioid medications (e.g. codeine, hydrocodone, oxycodone) to achieve a synergistic, and presumably opioid-sparing effect.
Although the exact site of activity and the mechanism of analgesic action are not clearly defined, acetaminophen seems to produce analgesia by elevation of the pain threshold. This may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate and substance P. Unlike aspirin or other non-steroidal anti-inflammatories, acetaminophen does not have anti-inflammatory action, does not increase bleeding tendency due to platelet aggregation inhibition, nor affect gastric mucosal protection mechanisms. The body processes acetaminophen in an efficient manner, with oral “regular-release” preparations rapidly and almost completely absorbed from the gastrointestinal tract, primarily in the small intestine. The relative bioavailability ranges from 85% to 98%. Acetaminophen is primarily metabolized by the liver, through a variety of primary and secondary pathways.
A frequent type of analgesic misuse is the self-prescribed increase of pain medications to achieve better pain control. This behavior frequently occurs with acetaminophen alone as well as with combination preparations. Recently, a significant amount of attention has focused on adverse effects of large doses of acetaminophen, specifically hepatic toxicity. Patients with chronic alcoholism and/or severe liver disease can develop hepatotoxicity even when acetaminophen use is at therapeutic doses.
Another possibly more important issue is that people may inadvertently self-administer acetaminophen in combination with prescription preparations that already contain the compound, resulting in excessive dosing. Although this may be perceived as an innocent and safe attempt to medicate for supplemental relief or breakthrough pain, the possible associated consequences can be severe, and may not differ from an overdose.
With the public perception of acetaminophen as an OTC medication with a high level of safety regardless of dosing, there has been recent controversy about the lack of public awareness with regard to potential risks of acetaminophen overdose. The Food and Drug Administration met in June 2009 with a joint panel of The Drug Safety and Risk Management Advisory Committee, The Non-prescription Drugs Advisory Committee, and The Anesthetic and Life Support Drugs Advisory Committee. The panel recommended that a “black box” warning be issued for prescription medications that combine acetaminophen with another drug.
What this “black-box” approach might not address is the issue about how important it is to know the composition of all the prescription pain medications taken, as well as the OTC products co-administered, as these can potentially put the person in a dangerous situation. For example, a patient on a combination acetaminophen/opioid prescription pain medication might coincidentally develop a febrile condition, and treat the hyperpyrexia with acetaminophen, without even considering the consequences of overdose.
On January 13, 2011, the Food and Drug Administration (FDA) announced that it will ask pharmaceutical manufacturers of prescription acetaminophen combination products to limit the amount of acetaminophen to no more than 325 mg per tablet or capsule to “reduce the likelihood of overdoses and the potential liver injury that can follow”. The restriction is to be phased in over 3 years and affects all prescription analgesics that contain both acetaminophen and another ingredient, such as codeine, oxycodone, and hydrocodone. Some of these combination products now have as much as 750 mg of acetaminophen per tablet or capsule. The FDA will also implement the “boxed warning” describing the risk of liver injury.
The new dose limitation does not apply to OTC pain relievers or other acetaminophen-containing medications, such as cold, sinus, or cough formulas. These can sometimes contain up to 650 mg of acetaminophen. The FDA has stated that information about potential liver injury is already required on OTC products, and that it is “continuing to evaluate ways to reduce the risk of acetaminophen related liver injury from OTC products. Additional safety measures relating to OTC acetaminophen products will be taken through separate action, such as a rulemaking as part of the ongoing OTC monograph proceeding for internal analgesic drug products.”
In addition to the limit of acetaminophen, the FDA provided additional information for patients and healthcare professionals regarding the use of acetaminophen:
- – Severe liver injury, including cases of acute liver failure resulting in liver transplant and death, has been reported with the use of acetaminophen.
- – Maximum total daily dose should be 4 grams/day in healthy patients.
- – Patients should be educated about the importance of reading all prescription and OTC labels to ensure they are not taking multiple acetaminophen-containing products.
- – Patients should not drink alcohol while on acetaminophen-containing medications.
The FDA states that “By limiting the maximum amount of acetaminophen in prescription products to 325 mg per dosage unit, patients will be less likely to overdose on acetaminophen if they mistakenly take too many doses of acetaminophen-containing products.”
Education is clearly the key so that patients are aware of medications they take and the impact that mixing substances (OTC and prescription) can have on their well-being.
- 1. 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. U.S. Food and Drug Administration. January 13, 2011. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm239821.htm. Accessed April 5, 2011.