Are Warnings Against NSAIDs in COVID-19 Warranted?

Nancy A. Melville and Lisa Nainggolan

March 17, 2020

UPDATED March 18, 2020 with new information — The European Medicines Agency (EMA) says there is currently "no scientific evidence" that nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, could worsen coronavirus disease.

EMA adds that it "is monitoring the situation closely and will review any new information that becomes available on this issue in the context of the pandemic."

The EMA statement follows a warning from French health officials that suggested grave adverse events have been reported with the use of NSAIDs, such as ibuprofen, in patients with COVID-19, and they recommend treatment instead with acetaminophen.

This warning provoked much discussion on social media, with varied reactions from around the world.

The Spanish Ministry of Health stated on Sunday there is no evidence that ibuprofen (or other NSAIDs) makes COVID-19 infection worse. It did state, however, that ibuprofen package inserts mention use of the drug might mask the symptoms of infections, which could delay diagnosis and cause patients to be diagnosed in more severe stages. They emphasize, however, that this refers to infections in general, not specifically to COVID-19.

And one US expert says evidence of risks to people with COVID-19 beyond those already well-known with infections in general and NSAIDs have not been established.

British physicians broadly agree, although the National Health Service there has now updated its advice to say they are recommending acetaminophen as a better choice for infection in general.

"There is currently no strong evidence that ibuprofen can make COVID-19 worse. However, until we have more information, people should take paracetamol to treat the symptoms of coronavirus, unless they have been told by their doctor that paracetamol is not suitable for them," it says.

However, it also stresses, "those currently on NSAIDs for other medical reasons (eg, arthritis) should not stop them," and "there appears to be no evidence that NSAIDs increase the chance of acquiring COVID-19."

And the EMA says: "When starting treatment for fever or pain in COVID-19, patients and healthcare professionals should consider all available treatment options including paracetamol and NSAIDs."

"Each medicine has its own benefits and risks which are reflected in its product information and which should be considered along with EU national treatment guidelines, most of which recommend paracetamol as a first treatment option for fever or pain."

Paracetamol is a generic term for acetaminophen commonly used outside the United States.

French Warn on Ibuprofen and COVID-19; EMA Reviewing Data

On March 14, the French government reported "serious adverse events" associated with NSAIDs in people with COVID-19. Soon after, the French Health Minister Olivier Véran tweeted that "taking anti-inflammatory drugs (ibuprofen, cortisone...) could be an aggravating factor of the [COVID-19] infection."

"If you have a fever, take paracetamol," he tweeted. "If you are already on anti-inflammatory drugs or in doubt, ask your doctor for advice."

An investigation requested by the French National Agency for the Safety of Medicines and Health Products (ANSM) in April last year found that NSAIDs can have an aggravating role in the event of severe infection, resulting in serious infectious complications, causing hospitalizations, sequelae, or even death, with NSAID use in such instances.

The EMA notes that in May 2019 its safety committee, the Pharmacovigilance Risk Assessment Committee (PRAC), started a review of the NSAIDs ibuprofen and ketoprofen following the investigation by the French agency.

"The PRAC is reviewing all available data to see if any additional measure is required," it now says.

Of note, France has tighter restrictions on the sale of NSAIDs than other countries, and beginning this year, the products, including paracetamol and ibuprofen, are no longer available over-the-counter in the country.

In a statement on its website, Reckitt Benckiser, manufacturer of the Nurofen brand of ibuprofen, said: "Appropriate use of ibuprofen and paracetamol is still currently being recommended by most European health authorities as part of the symptomatic treatment of COVID-19. Reckitt Benckiser is not aware of any evidence that ibuprofen adversely impacts the outcome in patients suffering from COVID-19 infection."

The company "has neither received new safety information nor been involved in the evaluation of any adverse events regarding the use of ibuprofen in COVID-19," it adds.

"As with any medicine, we would remind consumers and their caregivers to carefully read and follow the instructions provided on the packaging and in the patient information leaflet."

No Evidence of Any Unique Risk of NSAIDs in COVID-19

Gregory Poland, MD, a professor of medicine and infectious disease and director of the Vaccine Research Group at the Mayo Clinic, in Rochester, Minnesota, said that, without clarification of any new data detailing effects, additional risks of NSAIDs related to COVID-19 are questionable.

Poland told Medscape Medical News: "I think there is far inadequate information to make a blanket statement like that [which the French Health Minister has made]."

NSAIDs, often recommended to relieve fever and symptoms of influenza as well as COVID-19, are well-known to have potential adverse effects on the stomach and kidneys in the very groups considered at higher risk of COVID-19 — older patients and those with comorbidities or compromised immune systems. In those patients, acetaminophen is commonly recommended as an alternative to treatment of fever anyhow.

"I think what [the French] are recommending is an overextension of the known concerns," Poland observed.

"I know of no published data on the use of NSAIDs with COVID-19 that represents any sort of unique risk," he stressed.  

I think what [the French] are recommending is an overextension of the known concerns. I know of no published data on the use of NSAIDs with COVID-19 that represents any sort of unique risk.    Dr Gregory Poland

Poland cautioned against a rush to draw conclusions in times when stress and panic are exceptionally high. He relayed a report from a colleague in which four severe COVID-19 cases were described as being among patients who were taking NSAIDs, seeming to draw an association between the two.

"There was an inappropriate inference of cause and effect," he said. "This is a mistake we commonly see — people will assume causality and more often than not, it's not the case."

French Experts Stand Their Ground  

But in exclusive interviews with Medscape France, a rheumatologist and an infectious disease expert gave their take on the stance of their health ministry.

Francis Berenbaum, MD, PhD, a rheumatologist at Saint-Antoine Hospital in Paris told Medscape France that in patients with rheumatological diseases who are on long-term treatment with NSAIDs therapy should not be stopped unless a patient starts having COVID-19 symptoms such as fever.

For other people, if they develop a fever and COVID-19 symptoms, they should not take NSAIDs because it can worsen the disease (although he acknowledges this is also known in several other viral diseases including flu), so it's better to take paracetamol unless there is a liver condition that prevents the latter.

Meanwhile, Christian Perronne, MD, PhD, an infectious disease specialist in Garches, France, told Medscape France he believes the advice to avoid NSAIDs in COVID-19 infection is common sense.

Perronne told Medscape Medical News he has not personally witnessed cases of COVID-19 worsening with NSAIDs, noting that there is not, as yet, enough perspective in France, but said this has been demonstrated by Chinese results.

NSAIDs are not suitable for respiratory infections, he stressed. He said he never gives NSAIDs in principle in respiratory infections, only in exceptional cases, when you cannot do otherwise. 

UK: Acetaminophen Better for Some, But Not Necessarily Due to COVID-19

A number of UK experts agree that acetaminophen is a preferable choice over NSAIDs in those at risk for COVID-19 because of the known safety reasons.

"There is a good reason to avoid ibuprofen as it may exacerbate acute kidney injury brought on by any severe illness, including severe COVID-19 disease," Rupert Beale, MB, PhD, group leader in cell biology of infection at the Francis Crick Institute, London, UK, told the UK Science Media Center. But, he added, "There isn't yet any widely accepted additional reason to avoid it for COVID-19."

Tom Wingfield, PhD, a senior clinical lecturer and honorary consultant physician with the Liverpool School of Tropical Medicine, UK, agreed.

"In the UK, paracetamol would generally be preferred over NSAIDs such as ibuprofen to relieve symptoms caused by infection such as fever," he told the UK Science Media Center.

"This is because, when taken according to the manufacturer's and/or a health professional's instructions in terms of timing and maximum dosage, it is less likely to cause side effects."

He underscored that more clarity is needed to determine the significance of the message from the French Health Ministry regarding the effect of NSAIDs on COVID-19.

"It is not clear from the French Minister's comments whether the advice given is generic 'good practice' guidance or specifically related to data emerging from cases of COVID-19, but this might become clear in due course," Wingfield said.

Corticosteroids and COVID-19

Poland noted that the French Health Ministry also recommends against the use of cortisone in COVID-19, which is consistent with recommendations by the World Health Organization and Centers for Disease Control and Prevention.

"Corticosteroids, though having a different mechanism of action than NSAIDs, are still noninflammatory and therefore seem [ideal] to use in an inflammatory disease," he explained.

"But the reasons for the recommendation against them is the observation that with SARS I, they not only did not improve the clinical course, but in fact appeared to have short-term and mid-term adverse effects in delaying viral clearance," Poland said.

However, experts recommend that patients taking cortisone or other steroids for chronic diseases should not stop them, except on advice from their physician. This advice was reiterated by the French rheumatologist Berenbaus in his interview with Medscape Medical News.

Separately, the UK Society for Endocrinology has issued advice on coronavirus for patients with adrenal or pituitary insufficiency who are taking hydrocortisone or other steroids.

Poland has reported no relevant financial relationships.

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