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

Abstract

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.

Keywords: Epidemiology; Osteoarthritis; Outcomes research.

Figure 1

Study selection. *Included animal studies, non-biological science studies and human studies of paracetamol not reporting adverse events. †Included reviews, editorials and commentaries; types of study not in inclusion criteria; outcome measures other than those in inclusion criteria.

Figure 2

Mortality. The relative rate of all-cause mortality in patients taking paracetamol versus patients not taking paracetamol. The online supplementary material provides the references for the included studies.

Figure 3

Cardiovascular adverse events (AEs). The risk ratio of cardiovascular AEs (confirmed or probable non-fatal myocardial infarction, non-fatal stroke, fatal coronary heart disease or fatal stroke) in patients taking paracetamol versus patients not taking paracetamol. The online supplementary material provides the references for the included studies.

Figure 4

Gastrointestinal adverse events (GI AEs). The relative rate of upper GI AEs (gastroduodenal ulcers and complications such as upper GI haemorrhages) in patients taking paracetamol versus patients not taking paracetamol. The online supplementary material provides the references for the included studies.

Figure 5

OR of a decrease in estimated glomerular filtration rate of at least 30 mL/min/1.73 m² in patients taking paracetamol versus patients not taking paracetamol. The online supplementary material provides the references for the included studies.