Risks of acetaminophen have been 'underestimated'

Acetaminophen is the most widely used over-the-counter and prescription painkiller in the world. However, a new study published in the journal Annals of the Rheumatic Diseases suggests that the risks of this popular analgesic may have been underestimated by doctors.

Although the study links adverse events with acetaminophen use, the researchers remind that the overall risks of adverse events remain small.

The mechanism behind the painkilling effect of acetaminophen, or paracetamol, is largely unknown, although recent studies suggest that the drug inhibits the central nervous system from producing prostaglandin. 

Generally, acetaminophen is considered to be safer than other nonsteroidal anti-inflammatories (NSAIDs) and opiate analgesics.

However, last year, we looked at the results of a large randomized controlled trial published in The Lancet that found acetaminophen is no more effective than a placebo for managing acute lower back pain.

The benefit of acetaminophen for managing osteoarthritis has also been questioned in recent studies, which led researchers to make the observation that there is no recent data available on the risks of acetaminophen at standard doses.

To provide estimates on the true risks of standard doses of acetaminophen, researchers from the Leeds Institute of Rheumatic and Musculoskeletal Medicine in the UK conducted a systematic review of eight existing studies that had investigated the association between acetaminophen use and adverse health effects.

Two of the studies investigated risk of death associated with acetaminophen use, and one of them found an increased relative rate of mortality among people who had been prescribed the drug compared with people who had not.

Four of the studies found an increased risk of adverse cardiovascular events to be linked with acetaminophen use, four studies reported adverse renal events, and one study found a link with adverse gastrointestinal events.

Dose-response finding was consistent across studies, despite likely bias

The Leeds Institute researchers say that the eight observational studies are likely to contain biases. They explain that people who take acetaminophen on a long-term basis often have multiple existing medical problems that may also require other painkillers and medications.

Despite this potential confounding factor and the small number of studies included in the systematic review, the researchers say that they found a consistent dose-response relationship between acetaminophen use at standard doses and the kind of adverse events that are typically associated with other NSAIDs, including incidence of mortality and cardiovascular, gastrointestinal and renal adverse events.

"While these limitations are important to consider," the researchers write, "the striking trend of dose-response is consistent across multiple outcomes and studies."

The overall risks associated with these adverse events remain small, the researchers remind. They point out that with every decision to prescribe medication there is a risk versus benefit calculation and trade-off of efficacy versus tolerability.

"Prescribers need to be aware of patients' individual responses to [acetaminophen] and the observed increased toxicity with regular and higher dosing within standard analgesic dose ranges," the authors write, concluding:

"Based upon the data presented above, we believe the true risk of [acetaminophen] prescription to be higher than that currently perceived in the clinical community. Given its high usage and availability as an over-the-counter analgesic, a systematic review of [acetaminophen's] efficacy and tolerability in individual conditions is warranted."

Reference:

1.  Paracetamol: not as safe as we thought? a systematic literature review of observational studies, Emmert Roberts, et al., Ann Rheum Dis, doi:10.1136/annrheumdis-2014-206914, published online 2 March 2015.
2.  The BMJ news release, accessed 3 March 2015.