Acetaminophen in Pain Medicine

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]

Uses

• 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

Metabolism

• 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

Overdose

• 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.

REFERENCES:
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.