Paracetamol: Is it as safe as we thought?

Paracetamol (acetaminophen) is still safer than nonsteroidal anti-inflammatory drugs (NSAIDs), but there is concern about its potential for some side effects not usually considered related to paracetamol, according to a study published in the Annals of Rheumatic Diseases.

ConaghanLead author Philip Conaghan, MD, PhD, a professor with the Leeds Institute of Rheumatic and Musculoskeletal Medicine in England, and colleagues looked at literature examining large community cohorts followed over long periods of time and found 8 studies. The researchers screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal adverse events (AEs) in the general population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome.

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“These were all observational studies and certainly had potential biases including inclusion of people with serious problems, more use of medications and probably more use of unrecorded OTC medications like NSAIDs,” Dr Conaghan said.

Comparing paracetamol use versus no use, of 2 studies reporting mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of 4 studies reporting cardiovascular AEs, all showed a dose-response with 1 reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose-response with an increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of 4 studies reporting renal AEs, 3 reported a dose-response with 1 reporting an increasing OR of >30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43).

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“The findings were increased relative risks of the sort of side effects usually associated with NSAIDs-including hypertension and renal impairment; for most side effects, the relative risks increased with increasing doses of paracetamol,” he said. “While these may reflect the biases of the study designs, there is some plausibility as in recent years, as well as central nervous system effects, there is some evidence for a weak peripheral anti-inflammatory effect from paracetamol.

“I don’t believe on the basis of this study alone, we should have massive changes in our use of paracetamol,” Dr Congahan continued. “But a signal has been raised from this [necessarily imperfect] data. We really need a robust long-term study where all comorbidities and medications-including OTCs-are recorded stringently. We need to first examine the literature on its efficacy for individual conditions; where it is efficacious we can manage side-effects, as we are used to doing with most drugs.”