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

Abstract

ObjectivesWe conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol.MethodsWe 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.ResultsOf 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).DiscussionGiven 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.

Paracetamol (acetaminophen) with or without codeine or dihydrocodeine for neuropathic pain in adults

“…There are few or no data for a range of other common painful conditions, including dysmenorrhoea and neck pain. Moreover, accumulating evidence from observational studies indicates a considerable degree of paracetamol toxicity, especially at the upper end of standard analgesic doses (Roberts 2016).…”

“…Paracetamol alone is no better than placebo for low back pain (Saragiotto 2016), spinal pain, or osteoarthritis (Machado 2015), and its use has been challenged in cancer pain (Mercadante 2013). The assumed safety of paracetamol is also being challenged (Roberts 2016). …”

Managing cardiovascular risk in patients with inflammatory arthritis: practical considerations

“…In AS, the use of NSAIDs might reduce the risk of CV disease [Tsai et al 2015]. Paracetamol may increase CV mortality in the general population, but this must be confirmed after adjusting for concomitant NSAID use and channeling bias [Roberts et al 2015].…”

Authors' reply to letter by C. Steffen

“…'Increases blood pressure' In addition to the quotes in our article, we are now in the position to add the publication of Roberts et al (2015). Evaluating the controlled prospective cohort trials in which paracetamol was compared with placebo or no treatment, the authors could show an increase in blood pressure with long-term use of paracetamol.…”

“…Along with that the incidence of cardiovascular problems increased dose dependently. Similarly, kidney function (glomerular filtration rate) decayed in the paracetamol cohorts more than in controls (Roberts et al, 2015).…”