Letter to the Editor, European Journal of Pain. 4 July 2015
With disbelief I have read the article by Brune et al. (2014). The abstract starts with a breathtaking statement: paracetamol, the most widely used drug in the world, is probably one of the most dangerous compounds in medical use. If this were true, the reader would expect data, facts and a detailed scientific discussion. But the authors have presented a compilation of argumentative lapses of a kind that should be avoided in a scientific article. Some of these flaws (biased, selective or wrong citations) are presented below.
“…liver damage (including an increase of transaminases) which may occur even at permitted doses in apparently healthy consumers (Watkins et al., 2006; Walton, 2014)”. By ingenious wording, this statement suggests that the authors reported liver damage. Actually, Watkins and colleagues reported no liver damage: “Initiation of recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT elevations” and stated that the clinical importance of their findings was unclear. The second reference (Walton, 2014) is an educational Internet article mainly reiterating FDA warnings on the risk of paracetamol overdose by combination products.
“Kidney toxicity” seems so important that this term appears twice in a headline. But it is only is seen in 1–2% of cases of paracetamol intoxications (Mazer and Perrone, 2008). In therapeutic doses, however, it is regarded as safe even in patients with advanced chronic kidney disease (Evans et al., 2009).
“Increases blood pressure”: The authors fail to mention important aspects of the cited studies. The validity of one study (Sudano et al., 2011) has been debated for statistical problems and for their clinical relevance (Nguyen, 2011). In the other cited study, Forman et al. (2005) conclude: “Higher daily doses of acetaminophen and nonsteroidal anti-inflammatory drugs independently increase the risk of hypertension in women”. So why Brune et al. (2014) favour NSAIDs?
“Aggravates the risk of…myocardial infarction”: Cited is a study by Chan et al. (2006), which reported an elevated risk for use of paracetamol on ≥22 days per month, but not that by Rosenberg et al. (2003), which rather pointed to a protective effect, and the case–control study by de Abajo et al. (2014), in which NSAIDs, but not paracetamol, were associated with a risk for acute myocardial infarction.
“…diclofenac, ibuprofen, ketoprofen and naproxen … are, to say the least, not lethal at overdose!” and “..less toxic COX inhibitors can take over in most instances.” Moynihan (2002) counts 450 deaths by paracetamol per year in the United States. As the primary remedy to this hazard, Brune suggests replacing paracetamol by diclofenac, ibuprofen and other NSAIDs. But should it not be mentioned that 16,500 deaths per year were attributed to the use of NSAIDs in the United States (Wolfe et al. 1999)?
Although Brune formerly attributed to paracetamol a “superior overall gastrointestinal safety profile compared with NSAIDs” (Hinz et al., 2008), he now points out that paracetamol “…aggravates the risk of gastric ulcers”: The cited study of Rahme et al. (2008) on the contrary found that the small calculated risk for paracetamol was lower than that for traditional NSAIDs. Unmentioned remain the more recent publications which report the well-known gastric risk of NSAIDs and the absence of such risk for paracetamol (Castellsague et al., 2012; de Abajo et al., 2013).
“Recently, Brandlistuen et al. (2013) could demonstrate that children having been exposed to paracetamol showed physical and mental retardation in contrast to those from the same mothers who were not exposed to analgesics or to ibuprofen”. This investigation sought to identify risk factors for attention-deficit hyperactivity disorder (ADHD). This and other studies were important enough for the European Medicines Agency (EMA 2014) to reevaluate this risk. The EMA concluded that a causal relationship between paracetamol exposure during pregnancy and neurodevelopmental disorders cannot be established. The FDA has actually given a similar verdict: “Based on our evaluation of these studies, we believe that the weight of evidence is inconclusive regarding a possible connection between acetaminophen [paracetamol] use in pregnancy and ADHD in children.” (FDA, 2015).
“…investigations of…large databanks… indicate that paracetamol during pregnancy may…impair male fertility (Jensen et al., 2010; Snijder et al., 2012)”. This suggests that the cited studies deal with male fertility. But both studies were concerned with cryptorchidism, which is obviously not synonymous with infertility, a term that is not even mentioned in either paper.
“Indeed, ibuprofen was more effective and less toxic than paracetamol alone” (Doherty et al., 2011). This statement is simply at odds with the paper: The authors state that “the reported adverse events profile…was similar in all groups…” and they observed no statistically significant treatment differences between paracetamol 500 mg bid and ibuprofen 200 mg bid.
Finally, it would have been of interest to scrutinize the “recent epidemiological research”, which indicates that the argument “that paracetamol is a weak but harmless analgesic with low costs and low risks…cannot be sustained”. Unfortunately, the mentioned manuscript (Roberts et al., 2014, under review)” is not yet available.