By Chris Faubel, MD —


Names: acetaminophen / paracetamol (Tylenol)

  • Combinations with opioids
    • with tramadol = Ultracet
    • with hydrocodone = Norco, Vicodin, Lortab
    • with oxycodone = Percocet

Mechanism of Action Analgesic

  • Weak inhibitor of prostaglandin synthesis centrally [1]
  • Has other analgesic mechanisms at the spinal cord and cerebral cortex [4]


  • Drug of choice for relieving mild to moderate musculoskeletal pain (especially osteoarthritis)
  • Acute migraine headaches:  paracetamol 1,000-mg + metoclopramide 10-mg (Reglan) is as effective as sumatriptan 100-mg [5]

Benefit over NSAIDs

  • Does NOT interfere with the anti-platelet effect of aspirin (as ibuprofen does) – no increased risk of stroke
  • Does NOT cause renal or gastrointestinal problems

Synergistic Action

  • The combination or concurrent use of acetaminophen with various opioid analgesics (oxycodone, tramadol, etc.) has shown synergistic effects. [3] See the image below.
  • Brings together two different but complimentary mechanisms of analgesic action.
  • Benefit: Lower individual drug doses


  • Microsomal enzyme system in the liver (shared by other analgesics, anticonvulsants, antibiotics, and other drugs) – including the P450
  • When taken in normal doses in healthy patients, all metabolites are eventually broken down to non-toxic end products.
  • If the patient  is a “rapid metabolizer”, takes too much, or is a chronic alcohol abuser, the metabolite “NAPQI” accumulates and is toxic to hepatocytes.
    • Glutathione in the hepatocytes normally conjugates the NAPQI to make it non-toxic.
    • Chronic alcohol abuse (3 drinks per day) induces microsomal enzymes leading to a quicker production of NAPQI (patient’s glutathione can’t keep up).
  • Excretion = urine


  • The most common cause of acute liver failure [2]
  • Accidental overdoses are frequent because acetaminophen/paracetamol is found in many OTC products for the treatment of the flu, colds, and menstrual cramps. [for a list of products, click here]
  • Treated most commonly with intravenous N-acetylcysteine.
    • Acetylcysteine is a glutathione precursor.
  • Dosing (for older children and adults)
      • 325 to 650mg every 4-6 hours
        • Do NOT exceed
          • 4,000-mg in a 24-hour period
          • a single dose >1,000-mg
          • doses near 4,000-mg per day for > 10 days
          • a 2,000-mg daily limit in chronic alcohol abusers
  • In 2009, an FDA Advisory Panel recommended limiting the maximum daily dose to 3,000-mg, banning its combination with opioids (such as Vicodin and Percocet), and many other actions, but these are still being debated by the FDA.

1 – Graham et al.  “Mechanism of action of paracetamol”.  Am J Ther. 2005 Jan-Feb;12(1):46-55.

2 – Ostapowicz et al. “Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States”  Ann Intern Med. 2002 Dec 17;137(12):947-54.

3 – Gatti et al.  “Oxycodone/paracetamol: a low-dose synergic combination useful in different types of pain”  Clin Drug Investig. 2010;30 Suppl 2:3-14

4 – Loes, MW. (2005) “Chapter 10: Acetaminophen and Nonsteroidal Anti-Inflammatory Drugs”  Pain Medicine and Management: Just The Facts.  The McGraw-Hill Companies, Inc.

5 – Derry et al. “Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults”  Cochrane Database Syst Rev. 2010 Nov 10;11:CD008040.


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