Inappropriate use of ivermectin during the COVID-19 pandemic: primum non nocere!

Abstract

There is an ongoing debate worldwide about the possible benefits of ivermectin for the treatment and prevention of COVID-19. Some advocacy groups have concluded, based on limited, early studies, that ivermectin might be beneficial. They continuously lobby for the widespread use of ivermectin for the treatment and prevention of COVID-19, especially through social media. Based on their advice, some medical doctors of different specialties in many countries have recommended the use of ivermectin for COVID-19 treatment and prevention. On the contrary, official bodies such as the WHO, the European Medicines Agency, and Food and Drug Administration currently assert that available evidence does not support the use of ivermectin for the treatment or prevention of COVID-19 outside of well-designed randomized studies [[1]European Medicines Agency. EMA advises against use of ivermectin for the prevention or treatment of COVID-19 outside randomised clinical trials [cited 2021 Dec 4]. Available from: https://www.ema.europa.eu/en/news/ema-advises-against-use-ivermectin-prevention-treatment-covid-19-outside-randomised-clinical-trials.Google Scholar]. Ivermectin is a derivative of avermectins family of macrocyclic lactones that exhibits broad-spectrum antiparasitic activity. It is authorized for the treatment of onchocerciasis and strongyloidiasis in humans, as well as for veterinary use for a large range of animal species for internal and external parasites, and it has been approved by the Food and Drug Administration for these purposes [[2]Drugs.com. Ivermectin tablets. FDA professional drug information [cited 2021 Dec 4]. Available from: https://www.drugs.com/pro/ivermectin-tablets.html.Google Scholar]. In addition, several topical ivermectin formulations are permitted for the treatment of external parasites such as head lice, as well as skin disorders including acarodermatitis and rosacea. Ivermectin has shown in vitro activity against SARS-CoV-2; however, it is very important to mention that this in vitro activity occurred at much higher concentrations than those achieved in human plasma and lung tissue for usual doses [[3]Bray M. Rayner C. Noel F. Jans D. Wagstaff K. Ivermectin and COVID-19: a report in Antiviral Research, widespread interest, an FDA warning, two letters to the editor and the authors' responses.Antivir Res. 2020; 178: 104805Crossref PubMed Scopus (54) Google Scholar]. In animal models, ivermectin has been found to have anti-inflammatory effects; hence, it was hypothesized that this additional anti-inflammatory mechanism may also have some effects in the treatment of COVID-19 [[4]Yan S. Ci X. Chen N. Chen C. Li X. Chu X. et al.Anti-inflammatory effects of ivermectin in mouse model of allergic asthma.Inflamm Res. 2011; 60: 589-596Crossref PubMed Scopus (64) Google Scholar]. Although evidence was lacking that ivermectin concentrations achieved in in vitro SARS-CoV-2 research can be replicated in humans [[2]Drugs.com. Ivermectin tablets. FDA professional drug information [cited 2021 Dec 4]. Available from: https://www.drugs.com/pro/ivermectin-tablets.html.Google Scholar], these studies have been used as a basis to start the process of repurposing of this old drug for a novel infection. One of the first preprint papers that supported the idea ivermectin could be successful in a clinical-trial setting, was the study led by Elgazzar et al. However, on 14 July 2021, after members of the scientific community raised serious concerns about plagiarism, patient cloning, and data manipulation, the preprint server Research Square withdrew the paper because of ethical concerns. Numerous other studies on ivermectin's role in the treatment and prevention of COVID-19 have been published. However, the majority of the studies were observational, and it appears that some “controlled” experiments used convenience samples. The number of patients included was very small in most studies, and there was substantial variation in dose. Several concerns about these studies strongly limit the conclusions that can be drawn from the data presented. For example, it is impossible to adjust for indication bias in observational studies without an appropriate sample size. Two meta-analyses included many of these case series, observational or open-label studies [[5]Kory P. Gu Meduri Varon J. Iglesias J. Marik P.E. Review of the emerging evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of COVID-19.Am J Ther. 2021; 28: e299-e318Crossref PubMed Scopus (53) Google Scholar,[6]Bryant A. Lawrie T.A. Dowswell T. Fordham E.J. Mitchell S. Hill S.R. et al.Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines.Am J Ther. 2021; 28: e434-e460Crossref PubMed Scopus (67) Google Scholar]. However, a meta-analysis cannot correct for bias in the primary studies. The most stringent analysis was published by Popp et al. as a Cochrane database systematic review published in July 2021. Only randomized controlled trials (RCTs) comparing ivermectin to no therapy, standard of care, placebo, or another established intervention for COVID-19 treatment were included in this analysis. Fourteen RCTs on the treatment and prevention of COVID-19 in different settings were included in this meta-analysis. However, not all trials addressed the same specific outcomes (e.g. clinical worsening or need for supplemental oxygen). Therefore, the number of participants per outcome is often very small. The authors assessed RCTs for bias, using the Cochrane risk of bias 2 tool. They found very low-to low-certainty evidence for all outcomes [[7]Popp M. Stegemann M. Metzendorf M.I. Gould S. Kranke P. Meybohm P. et al.Ivermectin for preventing and treating COVID-19.Cochrane Database Syst Rev. 2021; 7: CD015017PubMed Google Scholar]. For inpatients as well as outpatients, there was no significant difference between the groups in terms of all-cause mortality and clinical worsening [[7]Popp M. Stegemann M. Metzendorf M.I. Gould S. Kranke P. Meybohm P. et al.Ivermectin for preventing and treating COVID-19.Cochrane Database Syst Rev. 2021; 7: CD015017PubMed Google Scholar]. Overall, the conclusion was that ‘reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials’ [[7]Popp M. Stegemann M. Metzendorf M.I. Gould S. Kranke P. Meybohm P. et al.Ivermectin for preventing and treating COVID-19.Cochrane Database Syst Rev. 2021; 7: CD015017PubMed Google Scholar]. The publications on the possible effects of ivermectin on the treatment and prevention of COVID-19 highlight some of the negative effects of the pandemic on scientific work. Many single-centre, observational studies were launched looking into research questions that they could not answer appropriately. Resources such as money and researchers' time and effort were used in redundant studies, as has been discussed before [[8]Paul M. Kalil A.C. Repurposed drugs for COVID-19: threshold and proof requirements for trials.Clin Microbiol Infect. 2021; 27: 1716-1717Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. The pandemic also underlined the need for international networks and trial platforms such as the WHO-led Solidarity trial that are able to start recruiting patients quickly if the need arises. Adhering to recommended doses, ivermectin is generally well tolerated. Common adverse effects associated with ivermectin include diarrhoea and nausea. However, significant symptoms can arise when ivermectin is overdosed. Symptoms of ivermectin overdose include gastrointestinal symptoms such as nausea, vomiting, and diarrhoea [[9]CDC Health Alert Network. Rapid increase in ivermectin prescriptions and reports of severe illness associated with use of products containing ivermectin to prevent or treat COVID-19 [cited 2021 Dec 4]. Available from: https://emergency.cdc.gov/han/2021/pdf/CDC_HAN_449.pdf.Google Scholar]. In addition, hypotension and neurologic effects such as decreased consciousness, confusion, hallucinations, seizures, coma, and death have been described [[9]CDC Health Alert Network. Rapid increase in ivermectin prescriptions and reports of severe illness associated with use of products containing ivermectin to prevent or treat COVID-19 [cited 2021 Dec 4]. Available from: https://emergency.cdc.gov/han/2021/pdf/CDC_HAN_449.pdf.Google Scholar]. Hospitalizations due to inappropriate ivermectin use and subsequent severe side effects have been noted in several European countries (personal communication). In comparison to the prepandemic baseline, calls to poison control centres due to ivermectin intake have increased five-fold in the United States, as reported by the CDC [[10]Bartoletti M. Azap O. Barac A. Bussini L. Ergonul O. Krause R. et al.ESCMID COVID-19 living guidelines: drug treatment and clinical management.Clin Microbiol Infect. 2022; 28: 222-238Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. Ivermectin may also magnify the effects of other substances that cause central nervous system depression, such as benzodiazepines, and it can interact with other medications, such as anticoagulants, even at levels approved for human antiparasitic usage. Furthermore, providing patients a false feeling of security might cause indirect harm, especially if they choose ivermectin instead of seeking hospital treatment for COVID-19 or being vaccinated in the first place. All guideline committees assessed the overall certainty of evidence for the use of ivermectin in the treatment and prevention of COVID-19 as low or very low after considering all of these factors [[1]European Medicines Agency. EMA advises against use of ivermectin for the prevention or treatment of COVID-19 outside randomised clinical trials [cited 2021 Dec 4]. Available from: https://www.ema.europa.eu/en/news/ema-advises-against-use-ivermectin-prevention-treatment-covid-19-outside-randomised-clinical-trials.Google Scholar,[2]Drugs.com. Ivermectin tablets. FDA professional drug information [cited 2021 Dec 4]. Available from: https://www.drugs.com/pro/ivermectin-tablets.html.Google Scholar,[10]Bartoletti M. Azap O. Barac A. Bussini L. Ergonul O. Krause R. et al.ESCMID COVID-19 living guidelines: drug treatment and clinical management.Clin Microbiol Infect. 2022; 28: 222-238Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. The ESCMID COVID guidelines committee on drug treatment and clinical management agreed on a strong recommendation against any use of ivermectin to treat COVID-19 patients [[10]Bartoletti M. Azap O. Barac A. Bussini L. Ergonul O. Krause R. et al.ESCMID COVID-19 living guidelines: drug treatment and clinical management.Clin Microbiol Infect. 2022; 28: 222-238Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. Misinformation on potential COVID-19 remedies disseminated by unofficial sources is widespread in many countries, which could lead to inappropriate and even dangerous use of this drug that is increasingly sold via illegitimate online pharmaceutical markets. Furthermore, the rise of false information in social media and in scientific literature continues to fuel vaccination hesitancy, mistrust in health authorities, anxiety, and the use of untested COVID-19 preventative and treatment measures, which is alarming. It is understandable that an inexpensive and widely available treatment for COVID-19 is desperately wanted all over the world. This is especially true for health care systems dealing with low vaccination rates. Even in a pandemic crisis, however, it is unethical and immoral to advocate for the broad use of a medication that has not been proven effective in clinical trials. Prescribing a substance just because it has not been shown to be ineffective goes against medicine's guiding principle of ‘first, do no harm.’ We should not ignore this principle, especially given the large amount of ongoing research on the benefit and harm of ivermectin in the treatment or prevention of COVID-19, which is still being carried out in this pandemic. The results from the available well-designed clinical studies so far do not support the commonly promoted benefits of ivermectin. The risk of injury by ivermectin is not balanced by any benefits of this drug in the treatment and prevention of COVID-19. Ivermectin has been shown to have negative side effects when used to prevent or treat COVID-19. As a result, ivermectin should not be used to treat COVID-19. Authors have no conflicts of interest. Study has no funding. No external funding has been received for this manuscript. AB and IZS conceptualized the paper and wrote the first draft. MB, OA, LB, OE, RK, JRPP, NP, JRB, MS, BGS, ST, PV and AMQ performed the literature search. All authors contributed to the manuscript writing. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved the final version of the manuscript for submission.