Evaluating the Efficacy of Adjunctive Therapies Used to Treat COVID-19: The Role of Famotidine, Melatonin, and Thiamine

Multiple OTC products have been proposed to treat coronavirus disease 2019 (COVID-19), but their true role remains unclear. H2-receptor antagonists (H2RA), melatonin, and thiamine are just some of the adjuvant treatments being evaluated for patients with COVID-19 due to their various immune-enhancing properties and possible antiviral effects.

H₂ Receptor Antagonists (famotidine)

Famotidine is an H2RA that has been suggested as a potential adjuvant therapy for patients infected with COVID-19. Previously, it was shown to inhibit HIV viral replication in vitro.¹ Famotidine’s theorized antiviral effects in COVID-19 are related to its suggested inhibition of 3C-like main protease (3CLpro), which may halt COVID-19 replication.²

In a preprint retrospective cohort study, the use of famotidine (both oral and intravenous) was associated with a reduced risk of intubation or death in COVID-19-positive patients.² The study included 1620 of patients, 84 of whom received famotidine.

Three different doses were evaluated: 10 mg (17%), 20 mg (47%), and 40 mg (35%). There was a 22% risk of death or intubation in patients who did not receive famotidine and a 10% risk in patients who did receive famotidine within 24 hours of hospitalization (HR: 0.42; CI: 0.21-0.85.)²

It is worth noting that proton pump inhibitors (PPIs) did not show the same benefits as famotidine in the article.² Famotidine’s overall good safety profile makes it an attractive adjuvant agent.³ It is also a therapeutic option for stress ulcer prophylaxis (SUP) in critically ill patients. Although additional studies are needed to confirm these positive effects, famotidine would be a reasonable choice in patients with COVID-19 who require SUP.

Melatonin

Melatonin is another non-prescription agent that is being proposed as a potential adjuvant treatment for COVID-19 infection.⁴ It is suggested that serious COVID-19 cases are marked by an excessive inflammatory and immune response leading to a cytokine storm.⁴

An article published online in March 2020 suggests that melatonin has demonstrated anti-inflammatory, anti-oxidative, and immunomodulatory effects, all of which could have benefit in COVID-19-infected patients.⁴ Melatonin is safe in most patients, with mild adverse drug reactions consisting of increased dizziness, headache, and sleepiness.⁵

Although no data are published yet, there are currently trials in progress evaluating the use of melatonin 2 mg daily as prophylaxis against COVID-19 infection for health care workers and melatonin.^6,7 These trials are occurring in Spain and Iran, respectively, and will not be completed until fall 2020 or summer 2021.^6,7

Thiamine (Vitamin B1)

Thiamine deficiency has been observed to be common in critically ill patients and has been linked to worse outcomes.^8,9 Insufficient thiamine levels lead to a shift to anaerobic metabolism and a subsequent rise in serum lactate levels, which in turn, can affect a patient’s acid-base status.⁸

There are no signs or symptoms specific to thiamine deficiency in critically ill patients, so it often goes unnoticed by physicians. It has been shown that thiamine depletion is associated with an almost 50% increase in mortality.⁹ Although, like many adjuvants, clinical trial data are needed with thiamine, it is proposed that since COVID-19 symptoms cause critical illness, affect multiple organ systems and the inflammatory cascade, and even escalate to acute respiratory distress syndrome, thiamine could prove beneficial in these patients.

Thiamine has a good safety profile with severe reactions being rare.¹⁰ Unfortunately, there are no current trials directly investigating the effect of thiamine in COVID-19 patients. There is a randomized, placebo-controlled trial underway designed to compare the use of thiamine combined with vitamin C and hydrocortisone in the treatment of sepsis and septic shock.¹¹

The results of this study may provide some insight into what role, if any, thiamine has in inflammatory reactions triggered by severe infections, such as COVID-19.

Conclusion

Although further studies are needed to establish a firm recommendation regarding the use of H2RAs, melatonin, and thiamine in the treatment of COVID-19 positive patients, their ease of access, relatively low price, and strong safety profiles makes them attractive choices as adjuvant therapies. It’s important to note that although reasonable pharmacologic mechanisms have been proposed for their role in COVID-19, there are limited data evaluating their actual efficacy in real patients with the novel virus.

What information is available is primarily focused on hospitalized patients rather than those with milder infections. As with so many issues with COVID-19, pharmacists need to remain aware that these OTC agents may end up playing a role in the treatment of the virus, but what and how important of a role will not be known for some time.

References

• Bourinbaiar AS, Fruhstorfer EC. The effect of histamine type 2 receptor antagonists on human immunodeficiency virus (HIV) replication: identification of a new class of antiviral agents. Life Sci. 1996;59(23):PL 365-70. doi: 10.1016/s0024-3205(96)00553-x.
• Famotidine Use is Associated with Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study. Daniel E Freedberg, Joseph Conigliaro, Magdalena E Sobieszczyk, et al. medRxiv 2020.05.01.20086694; doi: https://doi.org/10.1101/2020.05.01.20086694
• PEPCID (famotidine) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2011.
• Zhang R, Wang X, Ni L, et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020 Jun 1;250:117583. doi: 10.1016/j.lfs.2020.117583. Epub 2020 Mar 23.
• Andersen LP, Gögenur I, Rosenberg J, Reiter RJ. The Safety of Melatonin in Humans. Clin Drug Investig. 2016 Mar;36(3):169-75. doi: 10.1007/s40261-015-0368-5.
• ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). IdentifierNCT04353128, Efficacy of Melatonin in the Prophylaxis of Coronavirus Disease 2019 (COVID-19) Among Healthcare Workers. (MeCOVID); 2020 Apr 20 [cited 2020 Jun 15]; [about 3 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT04353128
• ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). IdentifierNCT04409522, Evaluation of Therapeutic Effects of Melatonin by Inhibition of NLRP3 Inflammasome in COVID19 Patients; 2020 Jun 1 [cited 2020 Jun 15]; [about 3 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT04409522
• Moskowitz A, Andersen LW, Huang DT, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care. 2018 Oct 29;22(1):283. doi: 10.1186/s13054-018-2217-4.
• Manzanares W, Hardy G. Thiamine supplementation in the critically ill. Curr Opin Clin Nutr Metab Care. 2011 Nov;14(6):610-7. doi: 10.1097/MCO.0b013e32834b8911.
• Thiamine Package Insert. Thiamine. In: Lexi‐Drugs, Lexi‐Comp Online [AUHSOP Intranet]. Hudson, OH: Lexi‐Comp/Wolters Kluwer Health. [updated June 8, 2020, cited 2020 Jun 15]. [about 8 p.]. Available from http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7755
• ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). IdentifierNCT03389555, Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis (ACTS) Trial; 2018 Jan 3, 2018 [cited 2020 Jun 16]; [about 3 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT03389555