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Paracetamol: not as safe as we thought? A systematic literature review of observational studies
  1. Emmert Roberts1,
  2. Vanessa Delgado Nunes2,
  3. Sara Buckner2,
  4. Susan Latchem2,
  5. Margaret Constanti2,
  6. Paul Miller2,
  7. Michael Doherty3,
  8. Weiya Zhang3,
  9. Fraser Birrell4,
  10. Mark Porcheret5,
  11. Krysia Dziedzic6,
  12. Ian Bernstein7,8,
  13. Elspeth Wise9,
  14. Philip G Conaghan10
  1. 1South London and the Maudsley Mental Health Trust, Maudsley Hospital, London, UK
  2. 2National Clinical Guideline Centre, London, UK
  3. 3Division of Rheumatology, Orthopaedics and Dermatology, Clinical Sciences Building, City Hospital, Nottingham, UK
  4. 4Northumbria Healthcare NHS Foundation Trust, Newcastle University, Ashington, UK
  5. 5Research Institute for Primary Care and Health Sciences, Keele University, Keele, UK
  6. 6Arthritis Research UK Primary Care Centre, Research Institute for Primary Care & Health Sciences, Keele University, Keele, UK
  7. 7Ealing Hospital NHS Trust Community Musculoskeletal Service, Clayponds Hospital, London, UK
  8. 8Gordon House Surgery, London, UK
  9. 9Encompass Healthcare, Washington, Tyne and Wear, UK
  10. 10Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds UK
  1. Correspondence to Professor Philip G Conaghan Leeds Institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, Leeds LS7 4SA, UK; p.conaghan{at}


Objectives We conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol.

Methods We searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome.

Results Of 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose–response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose–response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose–response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose–response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43).

Discussion Given the observational nature of the data, channelling bias may have had an important impact. However, the dose–response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.

  • Epidemiology
  • Outcomes research
  • Osteoarthritis

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