Re: Non-steroidal anti-inflammatory drugs and covid-19: Indomethacin or aspirin?
Long before the Covid19 pandemic, one of us had similar intense, protracted and violent coughing, but due to ramipril, an ACE Inhibitor (ACEI) which was inadvertently continued throughout this. One traumatic cough episode was followed by a thrombotic CVA, so anti-platelet therapy was started with aspirin at an intermediate 600mg daily dose. This abolished the cough for several weeks until aspirin was reduced to 75mg, when cough relapsed. The patient researched this at (1) and re-started aspirin at 600mg daily which abolished it; then after ramipril was at last stopped, reverted safely to 75mg.
This effect of aspirin at 600mg dose was established in 2000 by Tenenbaum et al. to be kinin-mediated (1,2). Further, aspirin in anti-platelet doses of 150mg or less was shown to be ineffective at reversing cough (3). This may be not well known because normally in clinical practice, a side-effect is treated by stopping the causal drug, not by prescribing a further drug.
Aspirin is a potent non-selective NSAID, and one other shown effective for ACEI-cough is indomethacin (4).
ACEI adverse reactions and Covid19 have many similarities:
● Cough is dry, hacking, exhausting and unresponsive to standard antitussives.
● Abnormalities of smell and taste are common to both
● ACEI-cough has 4x greater prevalence in black subjects (5) – similarly to Covid19
These should be unsurprising, as the principal target for cell entry by SARS-CoV-2 is now well-known to be the ACE2 receptor (6–8). SARS-CoV-2 infection consumes ACE2, which releases its control over kinin systems (6), detailed here as: “reduced ACE2 function in the lung … in turn activates B1 receptors with release of pro-inflammatory cytokines and intense lung inflammation and injury.” Covid19’s “dysregulation” of the Renin Angiotensin Aldosterone System is like an exploding dose of ACE Inhibitor, so could its symptoms also respond to these drugs?
The treatment of Covid19 cough is of high value even if only for symptoms, but it is also the herald symptom of massive painful inflammation with risk of lethal coagulopathy (6,7). Some researchers propose to suppress this by selective drugs such as icatibant to block the action of bradykinin (6,9) but do not appear to have considered aspirin or indomethacin. Similarly, this review of S Korean hospital cases (10) assesses 17 NSAIDs for harm in Covid19 – but neither aspirin nor indomethacin were included.
The role of NSAIDs in Covid19 is much debated (10–13), but we also note these Rapid Responses (14)
● by Rothstein, Liebowitz et al. describing over 60 cases, with substantial benefit of indomethacin to well-being and pain as well as to cough
● by Ioannou calling for more research, and citing some antiviral actions of indomethacin, first suggested in Amici’s 2006 work (16) on activity against SARS-CoV, which shares the ACE2 target.
We would add that indomethacin now seems to have in-vitro anti-SARS-CoV-2 activity, confirmed in-vivo on canine coronavirus, per pre-print (15). Indomethacin’s other anti-viral properties were detailed by Amici in 2015 (17), also reporting that this mechanism (to enhance PKR) does not apply to aspirin.
Since indomethacin is proven in ACEI-cough to work as does aspirin 600mg (4), the mechanism to suppress kinins is shared by both drugs, and so may be part of an action against SARS-CoV-2.
The role of steroids in Covid19 is clearer since the RECOVERY trial supported low-dose dexamethasone in more advanced disease - but found possible harm in earlier phases, per Fig 1b (18). This is discussed as due to high viral replication in earlier phases, which steroids may promote by suppressing innate immunity. For such a controlled suppression of inflammation, timing and duration are critical attributes, and may vary with phase of disease.
We agree that further research is urgently needed on indomethacin for its reported suppression of inflammation in Covid19. Its anti-coronaviral properties are less well-known, although it is long-established (so also cheap).
Current research on indomethacin is a small RCT in Iran https://en.irct.ir/trial/47520 , and on aspirin is only on anti-platelet doses. Naproxen (19) and lipid-ibuprofen (13) are under trial, but will not report till next summer. Meanwhile, it is hardly a re-purpose for GPs to prescribe for compassionate use, following the lead of Drs. Rothstein, Liebowitz et al. - and report.
1. Tenenbaum A, Grossman E, Shemesh J, Fisman EZ, Nosrati I, Motro M. Intermediate but not low doses of aspirin can suppress angiotensin-converting enzyme inhibitor-induced cough. Am J Hypertens [Internet]. 2000 Jul 1;13(7):776–82.
2. Fisman EZ, Grossman E, Motro M, Tenenbaum A. Clinical evidence of dose-dependent interaction between aspirin and angiotensin-converting enzyme inhibitors. J Hum Hypertens. 2002;16(6):379–83.
3. Davie AP, McMurray JJV V. Effect of aspirin on vasodilation to bradykinin and substance P in patients with heart failure treated with ACE inhibitor. Br J Clin Pharmacol [Internet]. 2002 Jan 11 [cited 2020 Jun 15];53(1):37–42. Available from: www.ncbi.nlm.nih.gov/pmc/articles/PMC1874546/
4. Rudd P, Rudd P. Indomethacin and nifedipine reduced coughing induced by captopril therapy. ACP J Club [Internet]. 1992 Sep 1;117(2):42. Available from: www.acpjournals.org/doi/abs/10.7326/ACPJC-1992-117-2-042
5. Elliott WJ. Higher incidence of discontinuation of angiotensin converting enzyme inhibitors due to cough in black subjects. Clin Pharmacol Ther. 1996;60(5):582–8.
6. van de Veerdonk FL, Netea MG, van Deuren M, van der Meer JW, de Mast Q, Brüggemann RJ, et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife [Internet]. 2020 [cited 2020 May 22];9. Available from: https://elifesciences.org/articles/57555
7. Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020;76:14.
8. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with covid-19. N Engl J Med [Internet]. 2020 Apr 23 [cited 2020 Jun 5];382(17):1653–9. Available from: www.nejm.org/doi/10.1056/NEJMsr2005760
9. Icatibant [Internet]. [cited 2020 Jun 22]. Available from: www.ncbi.nlm.nih.gov/pmc/articles/PMC2856042/
10. Eol H, Mph J, Lee H, Shin HJ, Choe YJ, Filion KB, et al. Association between NSAIDs use and adverse clinical outcomes among adults hospitalised with COVID-19 in South Korea: A nationwide study. Available from: https://doi.org/10.1101/2020.06.01.20119768
11. Little P. Non-steroidal anti-inflammatory drugs and covid-19. 2020 Mar 27 [cited 2020 May 26];368. Available from: www.bmj.com/content/368/bmj.m1185
12. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19 [Internet]. [cited 2020 Jun 21]. Available from: www.who.int/publications/i/item/the-use-of-non-steroidal-anti-inflammato...(nsaids)-in-patients-with-covid-19
13. LIBERATE Trial in COVID-19 - Full Text View - ClinicalTrials.gov [Internet]. [cited 2020 Jun 15]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT04334629
14. Rothstein R, Leibowitz J, Benjamin A, Clark C. Re: Non-steroidal anti-inflammatory drugs and covid-19 | The BMJ [Internet]. New York; 2020 [cited 2020 Jun 15]. Available from: www.bmj.com/content/368/bmj.m1185/rr-3 and Ioannou P: www.bmj.com/content/368/bmj.m1185/rr-0
15. Xu T, Gao X, Wu Z, Selinger DW, Zhou Z. Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo. bioRxiv [Internet]. 2020 Apr 5 [cited 2020 Jun 15];(December 2019):2020.04.01.017624. Available from: www.biorxiv.org/content/10.1101/2020.04.01.017624v1
16. Amici C, Di Caro A, Ciucci A, Chiappa L, Castilletti C, Martella V, et al. Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir Ther. 2006;11(8):1021–30.
17. Amici C, La Frazia S, Brunelli C, Balsamo M, Angelini M, Santoro MG. Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: Role of eIF2α kinase PKR. Cell Microbiol [Internet]. 2015 Sep 1;17(9):1391–404. Available from: www.ncbi.nlm.nih.gov/pmc/articles/PMC7162271/
18. Horbye P. Dexamethasone reduces death in hospitalised patients with severe respiratory complications of COVID-19 | University of Oxford [Internet]. [cited 2020 Jun 22]. Available from: www.ox.ac.uk/news/2020-06-16-dexamethasone-reduces-death-hospitalised-pa...
19. ENACOVID Trial Hopitaux de Paris Available from: https://clinicaltrials.gov/ct2/show/NCT04325633
Rapid Response:
Re: Non-steroidal anti-inflammatory drugs and covid-19: Indomethacin or aspirin?
Long before the Covid19 pandemic, one of us had similar intense, protracted and violent coughing, but due to ramipril, an ACE Inhibitor (ACEI) which was inadvertently continued throughout this. One traumatic cough episode was followed by a thrombotic CVA, so anti-platelet therapy was started with aspirin at an intermediate 600mg daily dose. This abolished the cough for several weeks until aspirin was reduced to 75mg, when cough relapsed. The patient researched this at (1) and re-started aspirin at 600mg daily which abolished it; then after ramipril was at last stopped, reverted safely to 75mg.
This effect of aspirin at 600mg dose was established in 2000 by Tenenbaum et al. to be kinin-mediated (1,2). Further, aspirin in anti-platelet doses of 150mg or less was shown to be ineffective at reversing cough (3). This may be not well known because normally in clinical practice, a side-effect is treated by stopping the causal drug, not by prescribing a further drug.
Aspirin is a potent non-selective NSAID, and one other shown effective for ACEI-cough is indomethacin (4).
ACEI adverse reactions and Covid19 have many similarities:
● Cough is dry, hacking, exhausting and unresponsive to standard antitussives.
● Abnormalities of smell and taste are common to both
● ACEI-cough has 4x greater prevalence in black subjects (5) – similarly to Covid19
These should be unsurprising, as the principal target for cell entry by SARS-CoV-2 is now well-known to be the ACE2 receptor (6–8). SARS-CoV-2 infection consumes ACE2, which releases its control over kinin systems (6), detailed here as: “reduced ACE2 function in the lung … in turn activates B1 receptors with release of pro-inflammatory cytokines and intense lung inflammation and injury.” Covid19’s “dysregulation” of the Renin Angiotensin Aldosterone System is like an exploding dose of ACE Inhibitor, so could its symptoms also respond to these drugs?
The treatment of Covid19 cough is of high value even if only for symptoms, but it is also the herald symptom of massive painful inflammation with risk of lethal coagulopathy (6,7). Some researchers propose to suppress this by selective drugs such as icatibant to block the action of bradykinin (6,9) but do not appear to have considered aspirin or indomethacin. Similarly, this review of S Korean hospital cases (10) assesses 17 NSAIDs for harm in Covid19 – but neither aspirin nor indomethacin were included.
The role of NSAIDs in Covid19 is much debated (10–13), but we also note these Rapid Responses (14)
● by Rothstein, Liebowitz et al. describing over 60 cases, with substantial benefit of indomethacin to well-being and pain as well as to cough
● by Ioannou calling for more research, and citing some antiviral actions of indomethacin, first suggested in Amici’s 2006 work (16) on activity against SARS-CoV, which shares the ACE2 target.
We would add that indomethacin now seems to have in-vitro anti-SARS-CoV-2 activity, confirmed in-vivo on canine coronavirus, per pre-print (15). Indomethacin’s other anti-viral properties were detailed by Amici in 2015 (17), also reporting that this mechanism (to enhance PKR) does not apply to aspirin.
Since indomethacin is proven in ACEI-cough to work as does aspirin 600mg (4), the mechanism to suppress kinins is shared by both drugs, and so may be part of an action against SARS-CoV-2.
The role of steroids in Covid19 is clearer since the RECOVERY trial supported low-dose dexamethasone in more advanced disease - but found possible harm in earlier phases, per Fig 1b (18). This is discussed as due to high viral replication in earlier phases, which steroids may promote by suppressing innate immunity. For such a controlled suppression of inflammation, timing and duration are critical attributes, and may vary with phase of disease.
We agree that further research is urgently needed on indomethacin for its reported suppression of inflammation in Covid19. Its anti-coronaviral properties are less well-known, although it is long-established (so also cheap).
Current research on indomethacin is a small RCT in Iran https://en.irct.ir/trial/47520 , and on aspirin is only on anti-platelet doses. Naproxen (19) and lipid-ibuprofen (13) are under trial, but will not report till next summer. Meanwhile, it is hardly a re-purpose for GPs to prescribe for compassionate use, following the lead of Drs. Rothstein, Liebowitz et al. - and report.
Colin Brown FRCGP FFCI Glasgow General Practitioner retd. colin.brown99@nhs.net
Glen Griffiths MSc Sunningdale Software Engineer griftech@gmail.com
1. Tenenbaum A, Grossman E, Shemesh J, Fisman EZ, Nosrati I, Motro M. Intermediate but not low doses of aspirin can suppress angiotensin-converting enzyme inhibitor-induced cough. Am J Hypertens [Internet]. 2000 Jul 1;13(7):776–82.
2. Fisman EZ, Grossman E, Motro M, Tenenbaum A. Clinical evidence of dose-dependent interaction between aspirin and angiotensin-converting enzyme inhibitors. J Hum Hypertens. 2002;16(6):379–83.
3. Davie AP, McMurray JJV V. Effect of aspirin on vasodilation to bradykinin and substance P in patients with heart failure treated with ACE inhibitor. Br J Clin Pharmacol [Internet]. 2002 Jan 11 [cited 2020 Jun 15];53(1):37–42. Available from: www.ncbi.nlm.nih.gov/pmc/articles/PMC1874546/
4. Rudd P, Rudd P. Indomethacin and nifedipine reduced coughing induced by captopril therapy. ACP J Club [Internet]. 1992 Sep 1;117(2):42. Available from: www.acpjournals.org/doi/abs/10.7326/ACPJC-1992-117-2-042
5. Elliott WJ. Higher incidence of discontinuation of angiotensin converting enzyme inhibitors due to cough in black subjects. Clin Pharmacol Ther. 1996;60(5):582–8.
6. van de Veerdonk FL, Netea MG, van Deuren M, van der Meer JW, de Mast Q, Brüggemann RJ, et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife [Internet]. 2020 [cited 2020 May 22];9. Available from: https://elifesciences.org/articles/57555
7. Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020;76:14.
8. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with covid-19. N Engl J Med [Internet]. 2020 Apr 23 [cited 2020 Jun 5];382(17):1653–9. Available from: www.nejm.org/doi/10.1056/NEJMsr2005760
9. Icatibant [Internet]. [cited 2020 Jun 22]. Available from: www.ncbi.nlm.nih.gov/pmc/articles/PMC2856042/
10. Eol H, Mph J, Lee H, Shin HJ, Choe YJ, Filion KB, et al. Association between NSAIDs use and adverse clinical outcomes among adults hospitalised with COVID-19 in South Korea: A nationwide study. Available from: https://doi.org/10.1101/2020.06.01.20119768
11. Little P. Non-steroidal anti-inflammatory drugs and covid-19. 2020 Mar 27 [cited 2020 May 26];368. Available from: www.bmj.com/content/368/bmj.m1185
12. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19 [Internet]. [cited 2020 Jun 21]. Available from: www.who.int/publications/i/item/the-use-of-non-steroidal-anti-inflammato...(nsaids)-in-patients-with-covid-19
13. LIBERATE Trial in COVID-19 - Full Text View - ClinicalTrials.gov [Internet]. [cited 2020 Jun 15]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT04334629
14. Rothstein R, Leibowitz J, Benjamin A, Clark C. Re: Non-steroidal anti-inflammatory drugs and covid-19 | The BMJ [Internet]. New York; 2020 [cited 2020 Jun 15]. Available from: www.bmj.com/content/368/bmj.m1185/rr-3 and Ioannou P: www.bmj.com/content/368/bmj.m1185/rr-0
15. Xu T, Gao X, Wu Z, Selinger DW, Zhou Z. Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo. bioRxiv [Internet]. 2020 Apr 5 [cited 2020 Jun 15];(December 2019):2020.04.01.017624. Available from: www.biorxiv.org/content/10.1101/2020.04.01.017624v1
16. Amici C, Di Caro A, Ciucci A, Chiappa L, Castilletti C, Martella V, et al. Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir Ther. 2006;11(8):1021–30.
17. Amici C, La Frazia S, Brunelli C, Balsamo M, Angelini M, Santoro MG. Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: Role of eIF2α kinase PKR. Cell Microbiol [Internet]. 2015 Sep 1;17(9):1391–404. Available from: www.ncbi.nlm.nih.gov/pmc/articles/PMC7162271/
18. Horbye P. Dexamethasone reduces death in hospitalised patients with severe respiratory complications of COVID-19 | University of Oxford [Internet]. [cited 2020 Jun 22]. Available from: www.ox.ac.uk/news/2020-06-16-dexamethasone-reduces-death-hospitalised-pa...
19. ENACOVID Trial Hopitaux de Paris Available from: https://clinicaltrials.gov/ct2/show/NCT04325633
Competing interests: No competing interests