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Paracetamol: a probably still safe drug
  1. Alessandro Battaggia1,
  2. Pierangelo Lora Aprile1,
  3. Iacopo Cricelli2,
  4. Diego Fornasari3,
  5. Andrea Fanelli4,
  6. Claudio Cricelli1,
  7. Francesco Lapi2
  1. 1Italian College of General Practitioners and Primary Care, Florence, Italy
  2. 2Health Search, Italian College of General Practitioners and Primary Care, Florence, Italy
  3. 3Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
  4. 4Unit of Anesthesiology and Pain Therapy, General Hospital S. Orsola Malpighi, University Hospital of Bologna, Bologna, Italy
  1. Correspondence to Dr Francesco Lapi, Research Director, Health Search, Italian College of General Practitioners and Primary Care, Via Sestese 61, Florence 50141, Italy; lapi.francesco{at}

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In 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.3 By doing so, we identified several major methodological pitfalls among the collected studies (table 1).

View this table:
Table 1

Risk of bias in observational studies included in Roberts's meta-analysis according to ACROBAT checklist3

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 cohort5 ,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: mortality6); by a U-shaped curve (outcome: mortality,7 GI haemorrhage7); by an ascending trend followed by a clamorous final reverse (outcome: …

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