A risk-benefit assessment of paracetamol (acetaminophen) combined with caffeine

Pain Med. 2010 Jun;11(6):951-65. doi: 10.1111/j.1526-4637.2010.00867.x.


Objective: To determine the risk: benefit of paracetamol combined with caffeine in the short-term management of acute pain conditions.

Design: Database searches were conducted to identify double-blind trials comparing paracetamol/caffeine with paracetamol alone (benefit analysis) and any data pertaining to hepatotoxicity of paracetamol when combined with caffeine (risk analysis).

Interventions: Paracetamol/caffeine (1,000 mg/130 mg) vs paracetamol (1,000 mg) alone.

Outcome measures: Assessment of benefit has been derived by meta-analysis. Information on the pain condition and number of patients studied, dosing regimen, study design and analgesic outcome measures (total pain relief scores) was extracted and dichotomous outcomes were obtained by calculating the number of patients in each treatment group who achieved at least 50% of the maximum total pain relief score. Assessment of risk has been made by appraisal of the literature.

Results: Eight studies from four papers provided sufficient quantitative data for satisfactory meta-analysis. The relative benefit (of achieving at least 50% pain relief) of paracetamol/caffeine vs paracetamol alone was 1.12 (95% Confidence Interval 1.05-1.19) across a number of acute pain states (dysmenorrhoea, headache, post-partum pain, and dental pain). Review of the effects of the combination of paracetamol and caffeine on the liver revealed no compelling data to suggest a clinically meaningful increase in hepatotoxicity with use of paracetamol/caffeine combinations.

Conclusions: Paracetamol/caffeine (1,000 mg/130 mg) is effective and safe for use in acute management of pain. The hepatotoxicity of overdoses of paracetamol results from its oxidative metabolism, caffeine does not produce any increase in oxidative metabolism of therapeutic concentrations of paracetamol.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / adverse effects
  • Acetaminophen / therapeutic use*
  • Analgesics, Non-Narcotic / adverse effects
  • Analgesics, Non-Narcotic / therapeutic use*
  • Animals
  • Caffeine / therapeutic use*
  • Central Nervous System Stimulants / therapeutic use*
  • Databases, Factual
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Therapy, Combination
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Pain / drug therapy*
  • Risk Assessment
  • Treatment Outcome


  • Analgesics, Non-Narcotic
  • Central Nervous System Stimulants
  • Acetaminophen
  • Caffeine