The authors and an outside expert recommend caution when interpreting the data, as they are observational in nature and are subject to uncontrolled confounders. That said, the authors do note that the dose - response curves seen for each adverse outcome examined suggest "a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses."
Emmert Roberts, from South London and the Maudsley Mental Health Trust, Maudsley Hospital, London, United Kingdom, and colleagues present their findings in an article published online March 1 in BMJ.
"Paracetamol is the most widely used over-the-counter and prescription analgesic worldwide. It is the first step on the [World Health Organization] pain ladder and is currently recommended as first-line pharmacological therapy by a variety of international guidelines for a multitude of acute and chronic painful conditions," the authors write.
They conducted a systematic literature review to determine the adverse event profile of paracetamol by searching Medline and Embase from the date of inception to May 1, 2013. They identified observational studies written in English that reported mortality, cardiovascular, gastrointestinal, or renal adverse events in adults in the general population who took standard analgesic doses of paracetamol.
Ultimately, they included eight of 1888 studies retrieved. All of the included studies were cohort studies. The researchers assessed study quality using Grading of Recommendations Assessment, Development and Evaluation. They pooled or adjusted summary statistics for each outcome.
Both studies that examined mortality risk among adults who took paracetamol and those who did not found an elevation in overall risk. In one study, the standardized mortality ratio was 1.9 (95% confidence interval [CI], 1.88 - 1.94) for those taking the drug. The other study showed an overall risk of 1.28 (95% CI, 1.26 - 1.30), as well as a dose-response increase in the relative rate of mortality from 0.95 (95% confidence interval [CI], 0.92 - 0.98) at the lowest exposure, compared with nonusers, to 1.63 (95% CI, 1.58 - 1.68) at the highest exposure.
Of four studies that reported cardiovascular adverse events, all found a dose-response, with one study demonstrating an increased risk ratio of all cardiovascular events from 1.19 (95% CI, 0.81 - 1.75) at the lowest exposure to 1.68 (95% CI, 1.10 - 2.57) at the highest.
One study that reported gastrointestinal adverse events found a dose-response with relative rate of gastrointestinal adverse events or bleeding increasing from 1.11 (95% CI, 1.04 - 1.18) to 1.49 (95% CI, 1.34 - 1.66).
Four studies reported adverse events; of those, three found a dose-response, with one that reported an odds ratio of 30% or more decrease in estimated glomerular filtration rate increasing from 1.40 (95% CI, 0.79 - 2.48) to 2.19 (95% CI, 1.4 - 3.43).
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