From the Guidelines
Acetaminophen works primarily by inhibiting cyclooxygenase (COX) enzymes in the central nervous system, with a preferential effect on COX-2, reducing the production of prostaglandins in the brain, which are mediators of pain and fever. The mechanism of action of acetaminophen is complex and involves multiple pathways, including the inhibition of COX enzymes, activation of descending serotonergic pathways, and interaction with the endocannabinoid system 1.
Key Points
- Acetaminophen has minimal peripheral anti-inflammatory effects and does not significantly inhibit prostaglandin synthesis in peripheral tissues, which explains why it relieves pain and reduces fever but lacks substantial anti-inflammatory properties.
- The central mechanism of action of acetaminophen explains why it is effective for pain relief and fever reduction while having fewer gastrointestinal side effects compared to NSAIDs.
- However, acetaminophen carries the risk of hepatotoxicity at high doses due to the production of the toxic metabolite NAPQI, and its use should be limited to a maximum of 4 g per day, with a limit of 325 mg per tablet, capsule, or other dosage unit in prescription products 1.
Clinical Considerations
- The FDA recommends that patients be advised to limit daily acetaminophen intake to a maximum of 4 g, and imposes a limit of 325 mg of acetaminophen per tablet, capsule, or other dosage unit in prescription products to reduce the risk of severe liver injury from acetaminophen overdosing 1.
- Due to concerns of hepatic toxicity, the NCCN panel suggests that providers consider limiting chronic administration of acetaminophen to 3 g or less per day 1.
From the Research
Mechanism of Action of Acetaminophen
The mechanism of action of acetaminophen is complex and not fully understood. However, several studies have proposed different theories:
- Inhibition of cyclooxygenase (COX) enzymes, specifically COX-3, which is a variant of COX-2 2
- Metabolization to N-acylphenolamine (AM404), which acts on the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid 1 receptors in the brain 3, 4
- Activation of the descending inhibitory serotonergic pathway 4, 5
- Interference with the oxidation state of cyclo-oxygenase, rather than binding to the active site 6
Analgesic Effects
The analgesic effects of acetaminophen are thought to be mediated by:
- Activation of TRPV1 receptors on terminals of C-fibers in the spinal dorsal horn 3
- Activation of cannabinoid receptors by AM404 4, 5
- Inhibition of prostaglandin synthesis in the central nervous system 5
Anti-Inflammatory Effects
Acetaminophen is not considered to possess significant anti-inflammatory activity due to its weak inhibition of COX enzymes 3, 2. However, some studies suggest that it may have anti-inflammatory effects in certain conditions, such as inflammatory pain 3.
Metabolism
Acetaminophen is metabolized to AM404, which is thought to be responsible for its analgesic effects 3, 4, 5. The metabolism of acetaminophen is complex and involves several enzymes, including cyclooxygenase and fatty acid amide hydrolase 5.