We thank Rainer Spiegel for his Correspondence (Aspirin as a painkiller in patients with a high cardiovascular risk profile. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-020-0398-4 (2020))1 on our Review (Cardiovascular effects and safety of (non-aspirin) NSAIDs. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-020-0366-z (2020))2. We share his concerns about the lack of effective and safe analgesic drugs and the potential increase in the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the wake of the opioid crisis in the USA.

Spiegel suggests that analgesic-dose aspirin might have a cardiovascular benefit as an alternative analgesic treatment to NSAIDs. In our Review, the primary focus was on commonly prescribed NSAIDs, and analgesic-dose aspirin is not commonly prescribed in the countries in which we practise, Denmark (Danish Health Data Authority) and the UK3, although aspirin is widely available without prescription. We are unaware of good evidence demonstrating a better cardiovascular benefit–risk balance with analgesic-dose aspirin than with NSAIDs. Industry-sponsored, randomized clinical trials and independent epidemiological investigations have focused on the gastrointestinal effects of analgesic-dose aspirin4,5,6.

From a practical-use perspective, the duration of analgesia with aspirin is short, and dosing every 3–4 h to a maximum dose of 3.6 g per 24 h is recommended7. Therefore, if aspirin were to be used for analgesia, problems with adherence and breakthrough pain are likely7. Importantly, an overdose of aspirin is highly toxic. A community-based, randomized, industry-sponsored study reported that aspirin was unlikely to be superior to ibuprofen as an analgesic and was associated with more adverse effects overall8; although, in another industry-sponsored study, analgesic-dose aspirin was reported to be well tolerated during short-term use (median 3 days)4.

In summary, we currently find no strong evidence in terms of the cardiovascular benefit–risk balance to support a recommendation for the use of analgesic-dose aspirin as an alternative to other NSAIDs. We agree with Spiegel that the feasibility and safety of analgesic-dose aspirin for pain management in patients with a high cardiovascular risk profile need to be tested in prospective, randomized trials.