What is the mechanism of action (MOA) and dosage of paracetamol (acetaminophen) for pain and fever relief?

From the Guidelines

Paracetamol (acetaminophen) relieves pain and reduces fever primarily by inhibiting cyclooxygenase (COX) enzymes in the central nervous system, which decreases prostaglandin synthesis, and its standard dosage for adults is 500-1000 mg every 4-6 hours as needed, not exceeding 4000 mg (4 grams) in 24 hours, as recommended by recent guidelines 1. The mechanism of action of paracetamol involves the inhibition of COX enzymes in the central nervous system, which leads to a decrease in prostaglandin synthesis, resulting in pain relief and fever reduction.

• Unlike NSAIDs, paracetamol has minimal peripheral anti-inflammatory effects, making it a preferred choice for patients who are at risk of gastrointestinal side effects.
• The standard dosage of paracetamol for adults is 500-1000 mg every 4-6 hours as needed, not exceeding 4000 mg (4 grams) in 24 hours, as recommended by recent guidelines 1.
• Children's dosing is weight-based, typically 10-15 mg/kg every 4-6 hours, not exceeding 5 doses in 24 hours.
• Paracetamol is available in various forms, including tablets, capsules, liquid suspensions, and suppositories, and can be taken with or without food.
• Maintaining consistent intervals between doses helps maintain therapeutic blood levels.
• Patients with liver disease, alcohol use disorder, or those taking certain medications should use reduced doses, as paracetamol can cause serious liver damage at excessive doses, as highlighted in a study published in 2019 1.
• The FDA recommends limiting 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, as stated in a guideline published in 2019 1.
• A recent study published in 2022 1 suggests that a daily dose of 2-3 g of acetaminophen is generally recommended for patients with liver cirrhosis, as they are at risk of metabolic disorder and prolonged half-life of acetaminophen.
• Overall, paracetamol is generally well-tolerated but can cause serious liver damage at excessive doses, so it's crucial not to exceed recommended amounts, as emphasized in a study published in 2016 1.

From the FDA Drug Label

Temporarily relieves minor aches and pains due to: headache muscular aches backache minor pain of arthritis the common cold toothache premenstrual and menstrual cramps Temporarily reduces fever The mechanism of action (MOA) of paracetamol is not explicitly stated in the provided drug label.

• The label only mentions the uses of paracetamol, including temporary relief of minor aches and pains, and reduction of fever.
• The dosage of paracetamol is also not specified in the provided text. 2

From the Research

Mechanism of Action (MOA) of Paracetamol

• Paracetamol is a common analgesic and antipyretic drug for management of fever and mild-to-moderate pain in infants and children, and it is considered as first-line therapy for the treatment of both according to international guidelines and recommendations 3.
• The mechanism of action of paracetamol is complex and multifactorial, and several aspects of the pharmacology impact its clinical use, especially in the selection of the correct analgesic and antipyretic dose 3.
• Paracetamol has a broad tolerability and is of particular value in the treatment of patients in whom nonsteroidal anti-inflammatory drugs are contraindicated such as aspirin-sensitive asthmatics and people at risk of gastrointestinal complications 4.

Dosage of Paracetamol

• To maximize efficacy and avoid delays in effect, use of the appropriate dose of paracetamol is paramount, with a recommended dose of 15 mg/kg for fever and pain management in children 3.
• For adults, paracetamol is generally well tolerated at recommended doses (≤4 g/day) in healthy adults and may be preferable to non-steroidal anti-inflammatory drugs that are associated with undesirable gastrointestinal, renal, and cardiovascular effects 5.
• No evidence supports routine dose reduction for older people, rather, dosing for adults who are older and/or have decompensated cirrhosis, advanced kidney failure, or analgesic-induced asthma that is known to be cross-sensitive to paracetamol, should be individualized in consultation with their physician 5.

Efficacy of Paracetamol

• Paracetamol is an effective analgesic for the treatment of moderate pain where it is chiefly indicated, as shown in placebo-controlled studies in the perioperative setting and other acute pain states 6.
• Paracetamol has a favourable efficacy-tolerability profile and is therefore recommended as a basic, first-line analgesic in acute pain states and as a valuable component in multimodal analgesia 6.
• However, paracetamol is probably grossly over-prescribed for fever management and its value more perceived than real, with limited and in some cases contraindicated use in fever management 7.

Safety Profile of Paracetamol

• Paracetamol seldom causes adverse events and reports of serious side effects are rare, with a concern of hepatotoxicity, but this is rare among adults who use paracetamol as directed, including people with cirrhotic liver disease 5, 4.
• Putative epidemiologic associations of paracetamol use with kidney or cardiovascular disease, hypertension, gastrointestinal disorders, and asthma largely reflect confounding biases and are of doubtful relevance to short-term use (<14 days) 5.