Paracetamol: not as safe as we thought? A systematic literature review of observational studies.
OBJECTIVE
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).


CONCLUSIONS
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.
South London and the Maudsley Mental Health Trust, Maudsley Hospital, London, UK.
Emmert
E
Roberts
National Clinical Guideline Centre, London, UK.
Vanessa
V
Delgado Nunes
National Clinical Guideline Centre, London, UK.
Sara
S
Buckner
National Clinical Guideline Centre, London, UK.
Susan
S
Latchem
National Clinical Guideline Centre, London, UK.
Margaret
M
Constanti
National Clinical Guideline Centre, London, UK.
Paul
P
Miller
Division of Rheumatology, Orthopaedics and Dermatology, Clinical Sciences Building, City Hospital, Nottingham, UK.
Michael
M
Doherty
Division of Rheumatology, Orthopaedics and Dermatology, Clinical Sciences Building, City Hospital, Nottingham, UK.
Weiya
W
Zhang
Northumbria Healthcare NHS Foundation Trust, Newcastle University, Ashington, UK.
Fraser
F
Birrell
Research Institute for Primary Care and Health Sciences, Keele University, Keele, UK.
Mark
M
Porcheret
Arthritis Research UK Primary Care Centre, Research Institute for Primary Care & Health Sciences, Keele University, Keele, UK.
Krysia
K
Dziedzic
Ealing Hospital NHS Trust Community Musculoskeletal Service, Clayponds Hospital, London, UK Gordon House Surgery, London, UK.
Ian
I
Bernstein
Encompass Healthcare, Washington, Tyne and Wear, UK.
Elspeth
E
Wise
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds UK.
Philip G
PG
Conaghan
D000082:Acetaminophen / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced*; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced*; D009026:Mortality; D064887:Observational Studies as Topic
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen
Epidemiology; Osteoarthritis; Outcomes research