COVID-19 and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
by Dr. David Borenstein M.D. 09/2021
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are among the most commonly used drugs worldwide. NSAIDs are medicines that treat a wide range of musculoskeletal illnesses including spinal disorders, osteoarthritis and inflammatory conditions like rheumatoid arthritis. NSAIDs effectively relieve pain, inflammation, and fever. A number of treatment guidelines for osteoarthritis, rheumatoid arthritis, and chronic low back pain recommend the use of NSAIDs for extended periods of time.
NSAIDs have a multitude of effects on the body. One of the most important is the inhibition of prostaglandins. The inhibition of prostaglandins results in the risks and benefits of NSAIDs. Prostaglandins have “housekeeping” functions of maintaining blood flow to the kidneys to sustain normal renal function and securing the protective barrier of mucous on the lining of the stomach to prevent ulcers. Prostaglandins also have the “induced” function in the setting of injury to facilitate the healing inflammatory response resulting in fever, swelling and increased blood flow.
COVID-19 and Non-steroidal Anti-Inflammatory Drugs (NSAIDS) – No Increased Risk
An ongoing concern involving individuals who suffer from rheumatic diseases including inflammatory and non-inflammatory disorders is whether their illness or their therapy increases the risk of dying from COVID-19 infection. In March 2020, a study from France suggested that the use of NSAIDS in COVID-19 patients was associated with increased mortality. As a result of this study, acetaminophen was suggested as a substitute for NSAIDS for symptoms of COVID-19 infection.1 At the time, a suggestion was made that additional investigation was needed to know if NSAIDS were, in fact, more deadly.
In response to the need for additional information, two studies were organized involving a British population of 536,423 current NSAIDS users and 1,927,284 non-users in the general population. In this first study, there was no evidence of difference in risk of COVID-19 related death associated with current NSAIDs use.
In the second study, a population of 1,708,781 people with osteoarthritis or rheumatoid arthritis, of whom, 175,495 were current NSAIDS users were included.2 A higher proportion of people aged 70+ years were included in this population than the general population In this group with rheumatic disease, a lower risk of COVID-19 related death associated with current use of NSAIDS versus non-use.
The mechanisms that may explain this outcome are not self-evident. An unproven possibility is the inhibition of attachment of the virus to cells with angiotensin 2 receptors. It would seem that the benefits of the use of NSAIDS for the control of clinical symptoms of osteoarthritis and RA do not increase the risk of a poor outcome in the setting of COVID infection.
Coronavirus – 19, the viral pathogen causing the current world pandemic gains entry to the lung where the virus replicates. The virus is thought to gain entry to the lung cells through attachment to angiotensin converting enzyme (ACE)-2 receptors. Angiotensin 2 is a hormone that regulates blood pressure by retaining salt and water by the kidney and tightening the channel in arteries throughout the body. This hormone may also induce inflammation in blood vessels and is a factor in hypertension-associated vessel damage. This damage is mediated through the release of adhesion molecules that make inflammatory cells stick to vessel walls, chemokines that direct cells to an area, and cytokines that activates immune cells to release inflammatory factors. A mechanism to control high blood pressure is to limit the production of angiotensin 2 by an ACE inhibitor [ACEI (blocking the transformation of angiotensin 1 to 2)], OR by blocking the ACE2 receptor (ARB).
Theoretically, the use of an ACEI or an ARB could increase the number of ACE2 receptors in response to their inhibition. Diabetes medicines (thiazolidinediones) and arthritis drugs like NSAIDs (ibuprofen) are also among those thought to increase ACE2 receptor numbers. This data is based upon test tube experiments, not in humans. A group of investigators who reviewed the early reports of deaths from COVID 19 found up to a third had hypertension and a fifth with diabetes.1 These authors speculated that the use of NSAIDs, ACEI, and ARBs would increase the risk of being infected by COVID 19 and having a more life-threatening course. Various health officials, including those in France and World Health Organization (WHO), recommended a halt in the use of NSAIDs based on a total of 365 patients, only a minority had hypertension and diabetes. Of interest was the fact that the treatment history of the individuals in these groups is not known.
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In response to this report, another group of investigators refuted the conclusion of stopping anti-hypertension therapy with a concern about upregulating the number of ACE2 receptors.2 Studies have demonstrated prevention of more severe lung damage after an injury in the setting of ARB therapy. A strong recommendation was made that anti-hypertensive therapy with ACEI and ARB drugs should not be discontinued. Uncontrolled hypertension remains a significant threat to health including the development of heart attacks and strokes.
In addition, the Food and Drug Administration reported no scientific evidence connecting the use of NSAIDs with worse COVID-19 outcomes.3 Another editorial found no evidence linking NSAIDs and lung or heart issues in the setting of COVID-19 infections.4 The use of NSAIDs may decrease the severity of a fever, but individuals can develop a fever while taking NSAIDs. The toxicities of NSAIDs include gastrointestinal bleeding, and hypertension because of prostaglandin inhibition in the stomach and kidney. These disorders occur in a very small percentage of individuals taking NSAIDs. The vast majority of individuals have no toxicity with NSAIDs.
The choice of using drugs depends on the benefits and risks associated with the agent. The decisions regarding the use of medicines is best done between an informed patient and a health professional who knows an individual’s history, physical condition, and personal preferences.
References:
- Fang L et al. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet 2020; [https://doi.org/10.1016/52213-2600(20)30116-8](https://doi.org/10.1016/52213-2600(20%2930116-8)
- Tignanelli CJ et al: Antihypertensive drugs and risk of COVID-19? Lancet 2020; https.//doi.org/10.1016/52213-2600(20)30153-3
- FDA Advisory -
- Little P. Non-steroidal anti-inflammatory drugs and covid-19. BMJ 2020;368:m1185 doi:10.1136/bmj.m1185
