Letter to the Editor

Editor, – Paracetamol is generally recommended as the first drug of choice in pain largely because of its safety profile and cost. But is it as safe as it seems?

The relative risk of upper gastrointestinal complications from paracetamol is 3.6 for doses greater than 2 g per day. This is compared to a relative risk of 2.4 for low to medium doses of non-steroidal anti-inflammatory drugs (NSAIDs) and 4.9 for high doses.1

The relative risk of hypertension with 0.5 g (or more) of paracetamol per day is 1.99 (1.39-2.85) in young women and 1.93 (1.30-2.88) in older women. For NSAIDs, the relative risk of hypertension is 1.60 (1.10-2.32) in young women and 1.78 (1.21-2.61) in older women.2

Should we be concerned at this data and is paracetamol a medication that should be taken without warnings being issued to the public?

David Vivian
Medical practitioner

Expert comment

Placebo-controlled trials show that paracetamol has no significant effect on the gastrointestinal tract.1 By contrast, a case-control study on paracetamol reported that there was a dose-related increase in gastrointestinal adverse reactions.3 We and several others concluded that the finding of gastrointestinal toxicity of paracetamol could be a biased result, a recognised hazard of case-control and observational studies especially when relative risks are low.3-5 Furthermore, another case-control study found that upper gastrointestinal bleeding was not associated with paracetamol6 indicating considerable uncertainty regarding paracetamol and gastrointestinal toxicity. Paracetamol may, however, cause upper gastrointestinal complaints such as dyspepsia,4 although this does not usually lead to cessation of treatment.

Regarding hypertension, controlled trials of paracetamol generally show no significant effect on blood pressure. Recent reviews recommend that paracetamol is suitable for use in patients 'who may be at increased risk for the blood pressure or fluid effects of NSAIDs'.7 However, other studies report that the intake of paracetamol is associated with an increased incidence of hypertension.8-10 This finding is not widely accepted and a comment published on one of the studies said, 'I await more compelling data prior to warning my patients that acetaminophen [paracetamol] may have adverse effects on blood pressure'.11 Furthermore, an epidemiological study found no such association between paracetamol and blood pressure.12 The reason that patients take regular doses of analgesics may be the confounding factor that explains the risk for increased blood pressure. This is a well known hazard associated with observational studies even when adjustments are made for possible confounding differences between exposed and non-exposed cohorts.7

For both questions on the adverse effects of paracetamol, the conclusion that more evidence is needed before changing clinical practice is still very reasonable.11

Garry G Graham
Honorary Visiting Professor
School of Medical Sciences
University of New South Wales

Richard O Day
Professor of Clinical Pharmacology
University of New South Wales and St Vincent's Hospital

Professor Graham has received funding from GlaxoSmithKline Australia for research on the mechanism of action of paracetamol. Professor Day has been a member of an advisory board for paracetamol (GlaxoSmithKline consumer) and is currently on an advisory board for over-the-counter ibuprofen (Reckitt Benckiser plc). Honoraria are deposited in audited trust funds of St Vincent's Hospital, Sydney.


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  2. Forman JP, Stampfer MJ, Curhan GC. Non-narcotic analgesic dose and risk of incident hypertension in US women. Hypertension 2005;46:500-7.
  3. Lanza FL, Codispoti JR, Nelson EB. An endoscopic comparison of gastroduodenal injury with over-the-counter doses of ketoprofen and acetaminophen. Am J Gastroenterol 1998;93:1051-4.
  4. Garcia Rodriguez LA, Hernandez-Diaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001;12:570-6.
  5. Graham GG, Scott KF. Tolerability of paracetamol. Drug Saf 2005;28:227-40 .
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  7. Lewis SC, Langman MJ, Laporte JR, Matthews JN, Rawlins MD, Wiholm BE. Dose-response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data. Br J Clin Pharmacol 2002;54:320-6.
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  11. Dedier J, Stampfer MJ, Hankinson SE, Willett WC, Speizer FE, Curhan GC. Non-narcotic analgesic use and the risk of hypertension in US women. Hypertension 2002;40:604-8.
  12. Forman JP, Rimm EB, Curhan GC. Frequency of analgesic use and risk of hypertension among men. Arch Intern Med 2007;167:394-9.
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  14. Kurth T, Hennekens CH, Sturmer T, Sesso HD, Glynn RJ, Buring JE, et al. Analgesic use and risk of subsequent hypertension in apparently healthy men. Arch Intern Med 2005;165:1903-9.