The authors, who are affiliated with the Ribeirão Preto Dental School (FORP-USP) and School of Pharmaceutical Sciences (FCFRP-USP), investigated the effects of celecoxib and indomethacin, non-steroidal anti-inflammatory drugs (NSAIDs) classified by the World Health Organization (WHO) as the first step on the analgesic ladder, alongside paracetamol.

In recent years, dentists at FORP-USP’s Dental Enamel Clinic, who research and deal with the problem on a daily basis, have observed a sharp rise in the number of children seeking treatment for pain, white or yellow tooth spots, and dental sensitivity and fragility. In some cases, simple chewing can fracture the children’s teeth. All these are classical symptoms of DEDs of the type known as enamel hypomineralization, whose causes are poorly understood.

As a result of this disorder, dental decay in the form of carious lesions appears sooner and more frequently in these patients, whose restorations are less adhesive and tend to fail more. Studies have shown they may have to replace restorations ten times more often over a lifetime than people with healthy teeth.

A coincidence aroused the researchers’ curiosity most of all: the patients’ ages. The first years of life, when DEDs form, are a period in which sickness is frequent, often with high fever. “These diseases are typically treated with NSAIDs, which inhibit the activity of cyclooxygenase [COX, a key inflammatory enzyme] and reduce production of prostaglandin [which also promotes inflammation],” said Francisco de Paula-Silva, a professor in FORP-USP’s Pediatric Department and last author of the article. “However, COX and prostaglandin are known to be physiological for dental enamel, and we therefore wondered whether these drugs interfered in the normal formation of this structure.”

The study was supported by FAPESP via three projects (10/17611-4, 14/07125-6 and 21/09272-0).

The researchers used rats to study the problem, as these animals have incisors that grow continuously, which facilitates analysis. The rats were treated with celecoxib and indomethacin for 28 days, after which practically no differences were visible to the naked eye in their teeth. However, when the researchers began extracting, they found that the teeth fractured more easily.

Analysis based on imaging and chemical composition suggested that dental mineralization had been affected. The teeth contained below-normal levels of calcium and phosphate, which are important to dental enamel formation, and mineral density was low.

When the researchers looked for the reasons for this, they found alterations in proteins required for mineralization and cellular differentiation, showing that the drugs had indeed affected the composition of the dental enamel.

Next steps

“Right now, the study at least offers us a clue to the identity of a new player that may be involved in the development of DEDs. Hitherto we’ve been totally in the dark,” said Paula-Silva. “We only achieved these important findings thanks to the efforts of FORP-USP’s Dental Enamel Clinic and collaboration with Lúcia Helena Faccioli, a professor at FCFRP-USP. She made a crucial contribution to our understanding of the role played by lipidic mediators related to inflammatory diseases that affect teeth.”

The group plan to conduct a clinical study with the aim of confirming the results of the research in the animal model. “We’re going to analyze the medical history of the children with DEDs and their use of these drugs, and we’ll set up a clinical study that will correlate the two datasets to see if the same thing happens to humans. If so, we can make recommendations on which drugs shouldn’t be used for which patients. We can also help work out an appropriate treatment protocol in future,” said Paula-Silva, comparing this situation with that of tetracycline, an antibiotic not recommended for children because it causes tooth discoloration.

Another important point to be addressed is indiscriminate use of over-the-counter drugs, a problem that appears to have worsened as pediatric care has become more common, although concrete information on this is not yet available.

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Both are well-known drugs that have been in regular use by millions worldwide for decades, and have now been widely used in patients with Covid-19.  Early clinical trials have demonstrated their effectiveness for this, and confirm their safety.

Indomethacin

We have set out the evidence for indomethacin for treating cough and pain on these pages previously.  Indomethacin use in Covid-19 was first reported in May of this year. Further evidence emerged last week when a preprint of a controlled trial of indomethacin versus paracetamol in hospitalised Covid-19 patients in India was published.  Patients with rt-PCR positive Covid-19 were offered the option of having indomethacin or paracetamol.  A well-matched group of controls was obtained by propensity scoring from amongst those who opted for paracetamol. In the indomethacin group one patient out of 72 required supplementary oxygen compared with 28 out of 72 in paracetamol group; resolution of symptoms (fever, cough and myalgia) was appreciably faster in the indomethacin group. For example, the median time to resolution of cough was 3 days with indomethacin but 8 days with paracetamol.

Cough is very distressing, and hard to treat with standard antitussives; it also transmits virus effectively by aerosol when ventilation is poor, as in most homes and older hospitals. Reduced transmissibility alone is now a reason to prefer indomethacin to paracetamol. To summarise:

• Indomethacin hastens symptomatic recovery and prevents deterioration in patients with mild to moderate disease if treated early
• Indomethacin reduces transmission of Covid-19 by coughing in those exposed to infected patients
• Indomethacin is licensed for use in pain and fever.
• Indomethacin relieves Covid-19 symptoms for patients who already use it in gout
• Its G-I risks are low in short courses, and are manageable with proton pump inhibitors (PPIs)

Ivermectin

The evidence for ivermectin was set out on this site in early December.  There have now been many controlled trials of ivermectin around the world, one spectacular natural trial (in France) and several examples of mass treatment in South America – with consistent, positive results. We note that Covid-19 home treatment kits using ivermectin have made available in India and Brazil. To summarise:

• Ivermectin prevents transmission and development of Covid-19
• Ivermectin hastens recovery and prevents deterioration in patients with mild to moderate disease treated early
• Ivermectin hastens recovery and reduces ICU admission and death in hospitalised patients in multiple studies
• Ivermectin leads to striking reductions in Covid-19 fatality rates only in those regions where the population uses it to prevent parasites
• Ivermectin has a good safety record

Doctors report in social media that they take ivermectin themselves if at all possible, both to protect themselves from, and to treat their own Covid-19 infection.

Why are these drugs not used in the UK?

Neither of these drugs is licensed for treatment of Covid-19: but, of course, few drugs are – that’s the problem with new diseases. However, a substantial and growing body of evidence attests to their effectiveness.

Neither of these drugs is recommended by the National Institute for Healthcare Clinical Excellence (NICE) – because in order to reach this status there would need to be a randomised, controlled trial (RCT) in the UK to determine the effectiveness of the drugs. This will take many months to approve, organise and analyse even with current infection rates.  The evidence from around the world appears to be disregarded. The search for perfect evidence, such as a large RCT, has become the enemy of the good.

A formal proposal was submitted to Covid19 Therapeutics Advisory Panel (CTAP) in October to suggest the inclusion of indomethacin in the RECOVERY trial – but there has so far been no substantive response to this.

Many doctors in the UK are reluctant to prescribe drugs “off-label” because of these considerations.  However, they are professionally allowed to prescribe unlicensed drugs if it is required to meet the specific needs of a patient and are “satisfied that there is sufficient evidence or experience of using the medicine to demonstrate its safety and efficacy.” In practice, most have followed the prevailing guidance i.e. tell patients to stay at home and take paracetamol or ibuprofen until they become breathless at rest – then call for help from NHS Direct.

This cautious approach is at odds with the precautionary principle during a pandemic, and is now throttling the nation’s response to Covid-19 and putting many people at risk of needless suffering.

Where does this leave us?

We are told that we have growing numbers of cases and face the imminent possibility of hospitals being overwhelmed with risk of doctors rationing treatments as the Lombardy situation is repeated here.

It has been argued that there should be four pillars to a pandemic response – 1. Contagion control (stop the spread), 2. Early home treatment to reduce hospitalisations and death, 3. Late stage hospital treatment and 4. Vaccination to achieve herd immunity.  Public health authorities (and therefore the media) have focused on three of these but have overlooked early home treatment. Hospital care should be a safety net for survival rather than the first place for treatment.

What could we do?

We should very quickly review the evidence for indomethacin and ivermectin and establish a protocol for early home treatment of covid-19 to reduce the numbers of late-stage hospitalisations.

Indomethacin could be rapidly provided to patients by community pharmacists by means of a patient group direction (PGD) or through an online referral to a prescriber. The mechanisms for these procedures already exist and schemes could be put in place quickly if there were the will to do it.

For ivermectin, steps should be taken immediately to authorise its use for Covid-19 prevention and treatment. It could be supplied through the same methods as indomethacin. Also, considering its safety, it could be made available for direct sale, as in South America.

In case the NHS, Directors of Public Health and the Government are unable to do all this it might be wise to get a last minute message up to Father Christmas to ask him to scratch unicorns, world peace etc. and just bring us indomethacin and ivermectin for early treatment of Covid-19 instead.

Dr Colin Brown is a researcher at Edinburgh Napier University and a former General Medical Practitioner.

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There is mounting evidence to support the use of indomethacin to control covid-19 symptoms. Since we reported the experience of physicians in New York with the use of indomethacin in early covid-19, further reports and real world findings have added weight to calls for a randomised controlled trial to determine the effectiveness of the drug in this context.

Here is the story so far:

Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that has been used for the past 50 years in millions of patients. It has analgesic and anti-pyretic effects. Indomethacin is now a generic drug that is widely available in most countries at low cost. In the United Kingdom it is a prescription-only medicine (POM).

It has been prescribed by doctors in New York for numerous patients with early covid-19 symptoms, with good results in over 60 patients. They found that patients obtained rapid relief from cough, chest pain and headache, sometimes after as little as two doses.¹

Indomethacin has been prescribed by a nephrologist in India to a series of 17 high-risk patients with early covid-19 symptoms (some of whom were immunocompromised) again with good results.²

A further trial of indomethacin in early covid-19 in more than 100 patients is now nearing completion in India. Clinicians in India report the drug has been used successfully in more than 1000 patients with early covid-19 symptoms.

The reported benefits of indomethacin – relief of cough, chest pain and headache, are achieved with low-moderate doses (25-50mg, two or three times a day) that are within the licensed dose range for indomethacin.  Treatment is usually only required for a few days.

A recent study identified nearly 740,000 patients with documented SARS-CoV-2 infection. Some 244 of these were taking indomethacin and 474 were taking celecoxib (a NSAID that, unlike indomethacin, does not inhibit prostaglandin E synthase 2 (PGES-2)). A comparison of matched groups showed that indomethacin users were less likely than celecoxib users to require hospitalisation or inpatient services (Odds ratio (OR) 0.25; 95% CI 0.08 – 0.76).³

The beneficial effects reported appear to relate to indomethacin and not to other NSAIDs, such as ibuprofen. Indomethacin was shown to have anti-viral activity against SARS in 2006 in the wake of the SARS-CoV outbreak.⁴ It was subsequently shown to be active against SARS-CoV-2 in vitro and against canine coronavirus in vivo.⁵ Importantly, the antiviral effects were seen at normal anti-inflammatory dose levels.

The evidence for the use of indomethacin for symptom control in patients with early covid-19 is now so strong that we can no longer afford to ignore it.

The use of indomethacin (25 – 50 mg twice a day) early in the course of covid-19 infection can reduce the severity and duration of covid symptoms and reduce the need for hospitalisation.

Much covid research has been directed at management of patients who are critically ill with covid-19; this drug offers the opportunity for upstream prevention of serious illness, at a very modest cost (£1.42 for 28 x 25mg capsules). Moreover, although not specifically authorised for use in covid-19, it is, like other NSAIDs, licensed for use in musculoskeletal pain and fever and could therefore be prescribed by general practitioners or prescribing pharmacists immediately.

If the drug were put into routine use there could be health benefits and considerable saving of NHS resources. This could result in an easing of restrictions and a move towards normality.

References

1. Rothstein R, Leibowtiz J, Benjamin A, Clark C. Rapid Response: Re: Non-steroidal anti-inflammatory drugs and covid-19. https://www.bmj.com/content/368/bmj.m1185/rr-3

2. Ravichandran R, Srinivasan S, Clark C. Low dose indomethacin for symptomatic treatment of covid-19. Int J Med Rev Case Rep. 2020; 4(Reports in Microbiology, Infectious Diseases and Dermatology): 69-70doi: 10.5455/IJMRCR.LOW-DOSE-INDOMETHACIN. doi:10.5455/IJMRCR.LOW-DOSE-INDOMETHACIN

3. Gordon DE et al.  Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Cite as: Science

10.1126/science.abe9403 (2020).

4. Amici C et al.  Indomethacin has potent antiviral activity against SARS coronavirus. Antivir Ther 2006; 11: 1021–1030

5. Xu et al Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo  April 2020 https://doi.org/10.1101/2020.04.01.017624.

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“The ACEI cough is stopped by aspirin and indomethacin – so both drugs should also work in early covid-19 infection”, he explains. Rothstein and Leibowitz chose indomethacin for its suggested anti-coronaviral actions, and reported that it rapidly stopped Covid cough, relieved pain and improved well-being.¹ “It is a surprise that any NSAID would stop cough, and they also noted that ibuprofen did not do so”, he adds.

Reference

1. Rothstein R, Leibowitz J, Benjamin A, Clark C. Re: Non-steroidal anti-inflammatory drugs and covid-19.  BMJ Rapid response  April 2020: www.bmj.com/content/368/bmj.m1185/rr-3

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