Paracetamol: a probably still safe drug
Authors: Alessandro Battaggia, Pierangelo Lora Aprile, Iacopo Cricelli, Diego Fornasari, Andrea Fanelli, Claudio Cricelli, Francesco Lapi
Journal: Annals of the Rheumatic Diseases (2016)

Paracetamol: a probably still safe drugIn a recent meta-analysis, Roberts and coworkers have raised several concerns about the safety profile of paracetamol. 1 The criticism was supported by a clear association between exposure and risk of major end points (all-cause mortality, cardiovascular disease (CVD), hypertension, gastrointestinal (GI) disorders, renal failure) and a clear demonstration of a dose-response effect.Although Roberts's message is not conclusive-authors themselves suggest the need of further meta-analyses-it surely has a relevant burden in terms of public health being paracetamol the most largely used drug as first-line therapy for pain disorders.We present a critical revision of Roberts's meta-analysis following a step-by-step analytical approach.First, the quality of cohort studies included in the meta-analysis is overtly and intrinsically low.The authors broadly ascribe the low degree of internal validity of studies collected for the meta-analysis using the GRADE method, 2 although this tool is likely unsuitable for quality assessment of non-experimental studies. 1 Instead, we adopted the Cochrane A Cochrane Risk Of Bias Assessment Tool (ACROBAT) checklist, which is specifically tailored on observational investigations. 3By doing so, we identified several major methodological pitfalls among the collected studies (table 1).Second, most of the discussed examples fail to demonstrate a convincing dose-response effect.A clear dose-response effect was only revealed for the increased incidence of hypertension estimated by two severely biased studies based on Nurse's Health Study cohort 5 9 (see the following paragraphs for the details).Notably, Roberts and coworkers support the presence of a dose-response gradient for studies where this relation was instead represented by a plateau (outcome: mortality 6 ); by a U-shaped curve (outcome: mortality, 7 GI haemorrhage 7 ); by an ascending trend followed by a clamorous final reverse (outcome: renal failure, 8 hypertension 9 ) and by a wavering and/or confusing relations (outcome: myocardial infarction, stroke, 7 renal failure 7 10 ).In addition, some of these trends-by admission of the same authors 6 7 -were also due to uncorrected confounding bias, namely confounding by indication.Third, every bias potentially afflicting the paracetamol research is poorly discussed.We briefly resume our consideration for each individual outcome.All-cause mortality: Roberts's results likely suffer from confounding bias in particular confounding by indication due to patients' prognosis.Paracetamol tends to be preferentially assigned to sicker and frailer patients, whose prognosis is likely worse; the effect of this confounder is easily explained by temporal trends of mortality rates.In Lipworth's research, 6 the standardised mortality ratios peak in the first year of follow-up as well as the crude mortality rates observed by De Vries's. 7In essence, sicker patients assigned to paracetamol died sooner only because of the worse basal prognosis.Hypertension: Two investigations performed using the Nurse's Health Study cohort 4 5 represent a classic didactic example of uncorrected detection bias.The outcome was in fact recorded through biennial questionnaires and the diagnosis of hypertension was made by patient's physicians.The pain-affected patients are therefore featured by a greater likelihood to see their doctors, received more prescriptions of analgesics and more diagnoses of hypertension.