Yesterday, researchers from Denmark released a preprint* suggesting that use of non-steroidal anti-inflammatory drugs (NSAIDs) is not associated with severity or mortality in COVID-19. However, this paper leaves the issue quite unsettled.
In Denmark, prescriptions are required for all NSAID use except ibuprofen in doses 200 mg or less in packs with no more than 20 tablets. Over-the-counter use of ibuprofen accounts for 15% of all ibuprofen use. As a result, most NSAID use is tracked nationally with databases on who had NSAID prescriptions filled.
Just over 9000 people tested positive for COVID-19 in this group, and just under 250 had a prescription for NSAIDs filled in the 30 days leading up to the test.
In the raw, unadjusted data, patients who filled a prescription for NSAIDs in the 30 days leading up to a positive COVID-19 test had a nearly identical risk of death compared to those who did not, but they had a 42 percent increased risk of hospitalization. This was statistically significant, meaning there is a low probability of observing an association that strong or stronger if it were simply a result of random chance.
Several other risks seemed to vary with NSAID use, but were not statistically significant: a 43% increased risk of ICU admission, a 61% increased risk of mechanical ventilation, and an 87% increased risk of renal replacement therapy. These are of the same or greater strength as the statistically significant 42% increased risk of hospitalization, but they weren't statistically significant because the number of people who fell into these risks was five or more times lower than those who were hospitalized. In other words, while 56 NSAID users were hospitalized, only 11 were admitted to the ICU, 10 were put on mechanical ventilation, and fewer than five were given renal replacement therapy. Larger sample sizes would have been needed to confirm or refute these associations, but the numbers don't look good.
On the other hand, in the statistically adjusted data, NSAIDs look neutral.
NSAID users were older, more likely to be diagnosed with overweight or obesity, and more likely to have osteoarthrosis, rheumatoid arthritis, or dysmenorrhea, and more likely to have been prescribed opioids or inhaled corticosteroids. They were less likely to have cardiovascular disease or dementia.
There were many other drugs and conditions that tended to differ between NSAID-users and -nonusers, but the differences were not statistically significant.
After adjusting for these potentially confounding variables, NSAID use was not statistically significantly associated with death, hospitalization, ICU, mechanical ventilation, or renal replacement therapy. While nothing was statistically significant, the risk of death or ICU was nearly identical, while the risk of hospitalization and mechanical ventilation was about 15% higher and the risk of renal replacement therapy was about 15% lower. This is consistent with a random distribution of these risks that is not associated with NSAID use.
In the abstract and the conclusions of the paper, the authors only focus on the adjusted data.
But statistical adjustments can be misleading. Factors one would expect to associate with pain and inflammation were often associated with both NSAID use and death. These include opioids, glucocorticoids, corticosteroids, immunosuppressants, overweight, and obesity. Unless we know for sure what the causal pathway is tying each factor to the risk of COVID-19 severity, we don't know for sure that making the adjustment is sound. Consider these two possibilities:
It is certainly clear that inflammation plays a central role in COVID-19, and so it is perfectly conceivable that inflammation drives NSAID use and COVID-19 severity independently, causing a spurious association between NSAIDs and COVID-19 severity.
But it is also within the realm of possibility that inflammation drives NSAID use, and that NSAID use drives worse COVID-19 outcomes, and that NSAID use explains a portion of the association between preexisting inflammation and COVID-19 severity.
If the first case is true, the statistical adjustments eliminate a spurious association. If the second case is true, the statistical adjustments obscure a true association.
Mechanistically, the issue is complicated. Ibuprofen, as noted by the authors, might raise levels of ACE2, the entryway for the virus into our cells. As I noted in my first newsletter on clotting and COVID-19, NSAIDs inhibit the enzyme cyclooxygenase (COX) and decrease levels of prostaglandin E2 (PGE2). This effect inhibits the replication of some viruses and hastens the replication of other viruses. As I noted in my newsletter on naproxen and COVID-19, naproxen is a specific NSAID that inhibits the replication of SARS-CoV-2, the coronavirus that causes COVID-19, likely at least in part for very specific reasons that do not generalize to other NSAIDs and are independent of its effects on COX and PGE2. Naproxen also inhibits blood clotting. Both of these make naproxen a good candidate to test for positive effects in COVID-19, but the antiviral effects may not generalize to other NSAIDs.
Ultimately we need randomized controlled trials to sort these things out. In the specific context of COVID-19, I am modestly bullish on naproxen and modestly bearish on other NSAIDs. These positions could easily change with new research.
Three key limitations of this study are that it is observational and cannot show cause-and-effect relationships, that not everyone who has a prescription filled actually uses the drug, and that it would likely be more relevant how the use during the infection impacted severity rather than use that included the 30 days prior to testing.
The Bottom Line
The conclusion of the authors was that their results do not support stopping the use of NSAIDs for well-indicated reasons just because of COVID-19, but that NSAIDs have well established side effects and “should be used in the lowest possible dose for the shortest possible duration for all patients.”
I agree with these conclusions but also believe that they downplayed the correlations between NSAID use and severity that showed up in the unadjusted data.
Naproxen has the best case so far out of all the NSAIDs for use against COVID-19, but that could easily change with newer research.
Until there are randomized controlled trials completed, the effect of NSAIDs should be considered uncertain. Right now, it makes sense to use them only when needed for standard purposes, and, in the words of the authors, “in the lowest possible dose for the shortest possible duration for all patients.”
Stay safe and healthy,
Chris
Please Support This Service
These research updates are made possible by purchases of The Food and Supplement Guide to the Coronavirus. The guide contains my most up-to-date conclusions about what we should be doing for nutritional and herbal support on top of hygiene and social distancing for added protection. Due to the absence of randomized controlled trials testing nutritional or herbal prevention, these are my best guesses for what is likely to work without significant risk of harm, based on the existing science. By purchasing the guide, you are enabling me to continue devoting my skills to the most important issue we now face. I am genuinely grateful for your contribution. You can purchase the guide using this link.
You can get the guide for free if you pre-order my upcoming book, Vitamins and Minerals 101: How to Get the Nutrients You Need on Any Diet (to be released when the COVID-19 crisis subsides) or when you join my membership program, the CMJ Masterpass, which is meant to help people with significant health and wellness expenditures consistently save money by returning marketing cost of the companies involved back to the members as rebates.
For other ways to support my work, please see here.
Disclaimer
I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
Subscribe
If you aren't subscribed to the research updates, you can sign up here.
Archive
You can access an archive of these updates here.
Comments and Questions
To leave a comment or question, please use the Facebook post for this newsletter.
*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.