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• W2112711596 abstract "AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Letters to the Editor demonstrate interest. We are pleased to learn of Steffens comments and questions and will answer on the basis of recent publications. Before we take up the issues raised, we want to make two general statements: Central to pharmacology is the request of a dose–response relationship of a drug effect. Consequently, it is meaningless to compare treatment effects of recommended antipyretic and analgesic doses of paracetamol (at up to 4 g/day) with anti-inflammatory (antirheumatic) doses of nonsteroidal anti-inflammatory drugs (NSAIDs), e.g. ibuprofen 2.4 g/day. High doses of NSAIDs as used in rheumatology cause more and other problems than low doses (i.e. ibuprofen up to 1.2 g/day). Anti-inflammatory effects can be achieved with paracetamol in animals at doses which would translate into lethal doses in man. Therefore, paracetamol is used at relatively low doses as an analgesic but not an anti-inflammatory drug. In law, it is praxis to decide in dubio pro reo. If we apply this rule to drug use, the one to be favoured (protected) is the human being (res) and not the drug. In dubio, a damnation of a drug should be made even on the basis of incomplete evidence if human health is at stakes and the drug is not without alternatives. But now our responses to Steffen: ‘… liver damage’ There is no doubt that paracetamol even at therapeutic doses may damage the liver. Proof that this takes place even in healthy young men exposed to therapeutic usual doses of paracetamol has been produced by Watkins et al. (2006). The sizeable increase in transaminases observed by Watkins is a sign of liver toxicity. Transaminases are released from dying liver cells. Their decay must not be regarded as harmless. ‘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). ‘… myocardial infarction’ Again in addition to the quotes in our review, we point out that the investigation of Roberts et al. demonstrates an increased risk of myocardial infarctions along with the use of paracetamol. The paper of Rosenberg et al. quoted by Steffen can in the authors' opinion not be used as an argument of a cardioprotective effect of aspirin but not of paracetamol (see literature of Steffen, Letter to the editor). ‘… diclofenac, ibuprofen, ketoprofen and naproxen …’ are not lethal at overdose. The estimates of death due to ALF caused by paracetamol in Western nations are probably much higher than the numbers given by Moynihan. In the United Kingdom about 250 inhabitants die from paracetamol every year. The estimates of death in the United States are around 400 per year. Latest data are to be found in Lee (2013), Blieden et al. (2014) or Bateman et al. (2014). As to the death rate caused by nonsteroidal anti-inflammatory drugs, the estimates of Wolfe et al. (1999) are useless in this context as well. Wolfe et al. intended to define means to decrease the toxicity of cyclooxygenase inhibitors at anti-inflammatory doses but not the incidence of events. ‘… gastrointestinal safety …’ It has been claimed that one of the advantages of paracetamol is the lack of gastrointestinal toxicity. Recent research has uncovered that paracetamol not only increases the gastrointestinal toxicity of other NSAIDs (Rahme et al., 2008) but also carries a genuine GI risk as discussed by Roberts et al. (2015) and De Vries et al. (2010). The latter author could not find more GI toxicity of ibuprofen as compared to paracetamol. Steffen quotes Castellsague and de Abajo who (see Steffens references) find no GI risk of paracetamol. Interestingly, Castellsague et al. in the 2012 paper do not even mention paracetamol. De Abajo finds no increased GI risk but this is in contradistinction to the data of García-Rodríguez and Hernández-Díaz (2001) who showed that doses ≥2 g per day increase the gastrointestinal risk of paracetamol. Maybe de Abajo et al. succumbed to a typical type 2 error? This would be plausible as the senior author in the de Abajo paper is J. García-Rodríguez – who also is the first author of the other paper. Again a hint towards a type-2 error. ‘… second generation effects …’ In addition to the publications quoted (Brandlistuen et al., 2013; Liew et al., 2014), a recent publication of Thompson from New Zealand (Thompson et al., 2014) confirms that children of mothers who had been consuming paracetamol during pregnancy showed impaired development after birth. It appears difficult to deny that there may be a problem. Also, Steffen objects to call cryptorchidism a signal of ‘impaired male fertility’. Text books state that fertility is decreased in men who suffered from cryptorchidism. These recent reports on second-generation effects caused administrators to consult. The EMA appears to have come to the conclusion that for the time being there is no reason to worry (bene-Chemie publicly announced ‘the EMA gave the all-clear’) – although serious doubts remain. Indeed, the FDA demands: ‘Women taking pain medicines who are considering becoming pregnant should consult with their health care professionals …’ [to us FDA pleads for changing the OTC status of paracetamol to Rx for women in childbearing age or during pregnancy – exactly what we would suggest (in dubio …)]. This request is further fostered by the many publications connecting paracetamol during pregnancy with an early and frequent incidence of asthma in the offspring (compare our review). ‘… ibuprofen was more effective and less toxic than paracetamol alone’ The statement refers to Doherty et al. (2011). If one reads the paper cautiously or goes directly to the commentary written by my co-worker and myself (Brune and Hinz, 2011), one finds that indeed ibuprofen at OTC dose (1.2 g/day) is more efficacious in OA and better tolerated than paracetamol alone (4 g per day). The combination of ibuprofen with paracetamol was not superior. A significant increase in transaminases took place in all groups receiving para-cetamol alone or in combination with ibuprofen, but not in the ibuprofen only group. ‘… paracetamol is a weak analgesic with liver toxicity but devoid of the classical unwanted drug effects of nonsteroidal and inflammatory drugs.’ This assumption cannot be sustained. To the contrary, several recent publications, including the manuscript of Roberts et al. (2015), add new evidence to the contention that paracetamol is obsolete. Bateman et al. (2014) provide evidence that real and putative cases of paracetamol overdose cannot in all cases be rescued by giving n-acetylcysteine – but cause enormous costs to the society. We have read the comments and questions by Steffen with interest and hope that we could help to resolve misunderstandings. We believe that the new evidence presented suggests limiting the use of this old, weak but toxic analgesic. References Bateman, D.N., Carroll, R., Pettie, J., Yamamoto, T., Elamin, M.E.M.O., Peart, L., Dow, M., Coyle, J., Cranfield, K.R., Hook, C., Sandilands, E.A., Veiraiah, A., Webb, D., Gray, A., Dargan, P.I., Wood, D.M., Thomas, S.H.L., Dear, J.W., Eddleston, M. (2014). Effect of the UK's revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment. Br J Clin Pharmacol 78, 610– 618. Blieden, M., Paramore, L.C., Shah, D., Ben-Joseph, R. (2014). A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States. Expert Rev Clin Pharmacol 7, 341– 348. Brandlistuen, R.E., Ystrom, E., Nulman, I., Koren, G., Nordeng, H. (2013). Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol 42(6), 1702– 1713. Brune, K., Hinz, B. (2011). Paracetamol, ibuprofen, or a combination of both drugs against knee pain: An excellent new randomised clinical trial answers old questions and suggests new therapeutic recommendations. Ann Rheum Dis 70, 1521– 1522. De Vries, F., Setakis, E., van Staa, T.P. (2010). Concomitant use of ibuprofen and paracetamol and the risk of major clinical safety outcomes. Br J Clin Pharmacol 70, 429– 438. Doherty, M., Hawkey, C., Goulder, M., Gibb, I., Hill, N., Aspley, S., Reader, S. (2011). A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis 70, 1534– 1541. García-Rodríguez, L.A., Hernández-Díaz, S. (2001). Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 12, 570– 576. Lee, W.M. (2013). Drug-induced acute liver failure. Clin Liver Dis 17(4), 575– 586. Liew, Z., Ritz, B., Rebordosa, C., Lee, P.C., Olsen, J. (2014). Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr, 168(4), 313– 320. Rahme, E., Barkun, A., Nedjar, H., Gaugris, S., Watson, D. (2008). Hospitalizations for upper and lower GI events associated with traditional NSAIDs and acetaminophen among the elderly in Quebec, Canada. Am J Gastroenterol, 103(4), 872– 882. Roberts, E., Delgado Nunes, V., Buckner, S., Latchem, S., Constanti, M., Miller, P., Doherty, M., Zhang, W., Birrell, F., Porcheret, M., Dziedzic, K., Bernstein, I., Wise, E., und Conaghan, P.G. (2015). Paracetamol: Not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis 0, 1– 8. Thompson, J.M., Waldie, K.E., Wall, C.R., Murphy, R., Mitchell, E.A. (2014). Associations between Acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years. PLoS ONE 9, e108210. Watkins, P.B., Kaplowitz, N., Slattery, J.T., Colonese, C.R., Colucci, S.V., Stewart, P.W., Harris, S.C. (2006). Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA, 296(1), 87– 93. Wolfe, M., Lichtenstein, D., Singh, G. (1999). Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. NEJM, 340(24), 1888– 1899. Volume19, Issue7August 2015Pages 1051-1053 ReferencesRelatedInformation" @default.
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