A new study published in the reputed British medical journal The Lancet has concluded that non-steroidal anti-inflammatory drugs (NSAID) such as Ibuprofen do not cause harm to Covid-19 patients.

“Policy makers should consider reviewing issued advice around non-steroidal anti-inflammatory drug (NSAID) prescribing and Covid-19 severity. NSAID use is not associated with poorer outcomes in patients admitted to hospital with Covid-19,” the study concludes.

“For clinicians and patients, our findings should provide reassurance that NSAIDs can be used as indicated in the community without increasing the severity of COVID-19,” the study states.

However, at the same time the study says, “Although use of NSAIDs could, in theory, be beneficial in patients with COVID-19, we did not identify any evidence to support this.”

“In this study, patients admitted to hospital with COVID-19 who were taking NSAIDs did not have more severe disease than did patients who were not taking NSAIDs. Mortality, critical care admission, respiratory support, and acute kidney injury were also not significantly different across matched NSAID treatment groups. We found no evidence of harm caused by NSAID use in patients admitted to hospital with severe Covid-19,” the study states.

Early on in the Covid-19 pandemic, questions were raised concerning the safety of NSAIDs in patients with COVID-19, with suggestions that these drugs were leading to more severe disease in some patients.

Early in the pandemic it was suggested that pre-existing use of NSAIDs could lead to increased disease severity in patients with Covid-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription.

Our data show that patients taking NSAIDs did not have more severe symptoms or poorer outcomes than those not taking NSAIDs. These data support community studies showing that NSAID users did not have higher rates of hospitalisation with Covid-19 and smaller studies of in-hospital outcomes, which found NSAID use was not associated with poorer outcomes. A propensity matched data linkage study of patients with osteoarthritis taking NSAIDs in the community setting found no difference in the risk of developing Covid-19 or dying from the disease.

The authors claim that to the best of their knowledge, this is the largest study of in-hospital outcomes of patients with COVID-19 to date. Considering all the evidence, if there was an extreme effect of NSAIDs on Covid-19 outcomes or severity, this would have been observed in one or more of the studies that have been done, including the present study.

The study is based on data collected from hospitals during the first wave of Covid-19 in the UK. It was funded by UK’s National Institute for Health Research and the UK Medical Research Council (MRC).

Limitations of study

The authors also state that a potential limitation of the study is the absence of information on the indication for NSAIDs and duration ofuse. These missing data make it difficult to know whether individuals were taking NSAIDs for long-term conditions, or symptomatic relief for COVID-19 symptoms. Similarly, it is unclear whether patients continued taking NSAIDs during their inpatient admission. “Therefore, we are unable to make any recommendations on whether NSAIDs should be continued after admission to hospital,” the study states.

To address this, we did a sensitivity analysis comparing use of ibuprofen to no NSAIDs or use of other non-ibuprofen NSAIDs, as ibuprofen use is most likely to be short-term. We observed no increase in poorer outcomes in those who used ibuprofen compared with those who did not use NSAIDs.

Older patients

Similarly, older patients, who are at greatest risk of adverse outcomes from Covid-19, might be less likely to be taking NSAIDs compared with other, more healthy and fit populations, as older patients with greater numbers of comorbidities are less likely to be prescribed NSAIDs because of their side-effect profile; therefore, our matching might not have incorporated this patient group fully.

However, as older patients are less likely to be taking NSAIDs and the safety debate concerns younger populations, this is unlikely to affect our results and their relevance to clinical practice.

There are several other important limitations to our study that must be considered. First, the most used NSAID was ibuprofen, which mightnot be generalisable to every country. Different NSAIDs are known to have different side-effect profiles; therefore, clinical trials of a specific compound might not be generalisable to an entire drug class.

Additionally, our data did not contain information on drug dosages or adherence, so we were unable to model dose–response data.

Finally, our data lack a non-SARS-CoV-2 comparator group to provide a temporal comparison with other critical illness or respiratory conditions. Future research could include a comparator group to investigate if NSAIDs modify or moderate outcomes of interest in patients with Covid-19 compared with other illnesses.

Although use of NSAIDs could, in theory, be beneficial in patients with COVID-19, we did not identify any evidence to support this.

Clinical studies have suggested that release of proinflammatory mediators in COVID-19—including interleukin (IL)-1β, IL-6, and CCL2—is associated with more severe disease.

Preclinical studies in non-COVID-19 models have found that release of these cytokines can be inhibited by treatment with NSAIDs, leading to discussion around whether NSAIDs might be useful as a therapy for COVID-19.

In these studies, NSAIDs have been shown to suppress IL-6 production and expression through various mechanisms, including suppression of prostaglandin E2, which upregulates production of IL-6 and IL-8.

Studies in bronchial epithelium have found that treatment with NSAIDs reduces expression of inflammatory mediators, including IL-6.

A clinical trial of dexamethasone, which also has been shown to modulate inflammation, albeit probably through a separate mechanism, has been shown to reduce mortality in patients with Covid-19. Other immunomodulatory therapies are being trialled, including the IL-6 inhibitor tocilizumab. Results from the REMAP-CAP and RECOVERY trials showed that tocilizumab reduced the requirement for organ support and improved survival in patients with Covid-19, with further trials underway.

Our study did not capture whether NSAIDs were continued in hospital, so we cannot make any recommendations on whether these should be withheld or continued after hospital admission.

There are important groups of patients who rely on NSAIDs for pain relief, including those with inflammatory joint diseases, bone pain, gout, postoperative pain, and menstrual pain, who would otherwise have few non-opioid options for pain relief. Taken together, clinicians should continue to prescribe and manage NSAIDs in the same way as before the COVID-19 pandemic began.

Future Research

Future research in this area should focus on whether NSAIDs sufficiently modulate inflammation in COVID-19, by using both basic science and clinical approaches using appropriate outcomes that are directly measured. If benefit or harm is identified, finding the cellular mechanisms responsible for these effects will be important to inform the biological understanding of COVID-19.

Finally, including groups that compare NSAIDs with alternative analgesics should be considered to provide evidence for clinicians and patients on the risks associated with alternative medications.