• Acetaminophen (APAP) is a non-opioid analgesic and antipyretic used to treat pain and fever

Mechanism of action:

  • Analgesia
    • COX1 and COX2 inhibition decreases prostaglandin synthesis 
    • AM404 metabolite activates cannabinoid 1 (CB1) receptor (inhibitor of endocannabinoid transport), and TRPV1 receptor in the brain and spinal cord
  • Antipyretic via inhibition of hypothalamic heat-regulating center
Clinical Use: 
  • Acetaminophen is a commonly used first line agent for multimodal analgesia in treatment of acute pain, cancer pain, or perioperative enhanced recovery after surgery (ERAS) pathways
  • Formulations: PO, IV, and PR
  • Cost of IV formulation ($29.26)  is substantially higher than PO ($0.04) or PR ($1.31), with no clinically significant differences in efficacy


  • PO or PR 325-650mg q4-6h or 1g q6h
    • IV 
      • If > 50kg: 650mg q4h or 1g q6h
  • If < 50kg: 12.5mg/kg q4h or 15mg/kg q6h

Maximum dosing:

  • 4g/day for adults with normal liver function
  • 3g/day considered if longer duration (>7days)
  • 2g/day in alcohol abuse, malnutrition, fasting, low body weight, advanced age, febrile illness, liver disease
  • Onset: PO/PR 1hr, IV 15min (analgesia)
  • Duration: PO/IV analgesia 4-6hr, IV antipyretic >6hr
Special Considerations: 
  • The most concerning side effect is acetaminophen-induced hepatotoxicity due to supratherapeutic dosing. Special attention must be given to medications in combined formulations.
  • Contraindications include: hypersensitivity reactions, severe hepatic impairment, active alcohol use, or severe active hepatic disease
  • Drug interactions: Acetaminophen may cause a small increase INR in patients taking warfarin
  • Kidney disease: No dosage adjustments needed for AKI/CKD or dialysis patients including iHD, CRRT, PD
  • Liver disease: Dose reduce max 2g/day in cirrhosis. Avoid in patients with cirrhosis who are actively drinking, malnourished or fasting. Avoid in severe alcoholic hepatitis or acute liver injury.
  • Pediatrics: 10 to 15 mg/kg/dose every 4 to 6 hours as needed. Maximum daily dose: 75 mg/kg/day not to exceed 4,000 mg/day.
  • Breastfeeding: Generally considered safe when taken at usual doses

image of pills


  1. Ohashi N, Kohno T. Analgesic effect of acetaminophen: a review of known and novel mechanisms of action. Front Pharmacol. 2020;11:580289.
  2. Bourgeois FT, Graham DA, Kesselheim AS, Randolph AG. Cost implications of escalating intravenous acetaminophen use in children. JAMA Pediatr. 2019;173(5):489.
  3. Wick EC, Grant MC, Wu CL. Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques: a review. JAMA Surgery. 2017;152(7):691-697.
  4. Helander EM, Menard BL, Harmon CM, et al. Multimodal analgesia, current concepts, and acute pain considerations. Curr Pain Headache Rep. 2017;21(1):3.
  5. Portenoy RK, Ahmed E, Keilson Y. Cancer pain management: Use of acetaminophen and nonsteroidal antiinflammatory drugs. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA.