Medication Prescribing in Time of COVID, Unproven Remedies, Overstepped Autonomy, Known Harms: A Toxicologic Argument Against Ivermectin for COVID-19

Noah Berland, MD MS, Mehruba Anwar Parris, MD FAAEM

It has always been attributed to Paracelsus the toxicologic axiom that the dose makes the poison, one of the main tenets of modern day medical toxicology. And today, toxicologists are more than familiar with the EBM world’s issues with a large proportion of toxicologic research and treatments, so it is us toxicologists that are possibly the most informed on the weaknesses to be aware of when trying to treat a disease process without good evidence. In toxicology the reasons to provide treatment recommendations that are not based on randomized controlled trials are the following:

• The current treatment is well established with studies/case series that demonstrate a benefit and it would be unethical to withhold the treatment to perform a trial.

• The overdose is lethal and withholding any treatment is likely to cause death, and the mechanism of the treatment is biologically plausible.

• There is no other alternative treatment and it is believed that the potential benefits outweigh the risks.

Treating patients with COVID-19 using ivermectin does not follow any of the above three points. This has been true for a number of months. At present there are three systematic reviews that we are aware of, 1) is a Cochrane Review 1 showing no statistical benefit and clearly relates the clear uncertainty and poor quality of studies, 2) by Roman et al. 2 also showing no benefit, noting the paucity and poor quality of evidence, and 3) Bryant et al. 3 with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials. AREAS OF UNCERTAINTY: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID- 19 infection. DATA SOURCES: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trialsinvolving 3406 participants met review inclusion. THERAPEUTIC ADVANCES: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19- 0.73; n = 2438; I2 = 49%; moderate-certainty evidence which includes many non-peer-reviewed studies, performs questionable statistical techniques, and includes the now retracted Elgazzar et al paper, showing possible statistical significance, but even on rudimentary viewing of the results, does not appear to hold up. Lawrence et al. summarized the inherent risks in relying on meta-analyses of poor-quality data best in their correspondence in Nature titled “The lesson of ivermectin: meta-analyses based on summary data alone are inherently unreliable.” Yet, many physicians continue to prescribe ivermectin to their patients. Just as in the opioid overdose epidemic, we physicians are not blameless on promulgating this false hope, with prescriptions up from a pre-pandemic baseline of about five thousand a month, week to the week of August 13 th of 88 thousand prescriptions, a 24-fold increase (Figure 1). 4 The American Board of Emergency Medicine recently released a statement stating that spreading misinformation. 5 It is the role of physicians, and as an emergency medicine physician and toxicologist, to educate and inform our patients and provide the best possible care, which for most people was found on the internet, you can certainly see the surge in internet searches for ivermectin since the start of the COVID-19 pandemic, up 100 fold, while searches for scabies (one of the FDA approved indications) have not increased (Figure 2). 6

As toxicologists and emergency physicians, we must educate and dispel this disinformation. To help better inform emergency medicine physicians, we would like to review some of the basics of ivermectin. Ivermectin is an avermectin, which is a class of potent anthelmintic and insecticidal agents. Avermectin earned its discoverer Dr. Satoshi Omura a Nobel prize in medicine due to its effectiveness in treating river blindness, lymphatic filariasis, and other parasitic diseases. It is even on the WHO’s essential drug list, which also goes into exhausting supplies and likely increasing the cost of an essential drug that poorer nations require for proven susceptible diseases. 7

A: Ivermectin tablets are approved for use in humans for the treatment of some parasitic worms (intestinal strongyloidiasis and onchocerciasis) and ivermectin topical formulations are approved for human use by prescription only for the treatment of external parasites such as headlice and for skin conditions such as rosacea.

Ivermectin is FDA-approved for use in animals for prevention of heartworm disease in some small animal species and for treatment of certain internal and external parasites in various animal species. Humans should not take animal drugs, as the FDA has only evaluated their safety and effectiveness in the particular species for which they are labeled. Using these products in humans could cause serious harm.

Avermectins, including ivermectin, generally function by amplifying the effects of invertebrate-specific gated chloride channels at the neuromuscular junction, leading to hyperpolarization and subsequent paralysis. 8 This is generally well tolerated in mammalians, but as Paracelsus postulated, the dose makes the poison, at higher doses this specificity for the invertebrate receptor can be lost and avermectins can become more promiscuous. It can lead to effects on mammalian GABA-A receptors but is fairly non-specific and also have an effects on glutamate and possibly GABA-B receptors. 8 These effects in higher doses, is what causes the main known toxicity of avermectins in humans, namely encephalopathy and coma. The effects can be greatly potentiated or altered via drugs that impact the blood brain barrier, especially p-glycoproteins modulators, which regulate uptake and efflux across the blood brain barrier. 8 Further inflammation may weaken the blood brain barrier increasing the risk of neurotoxicity. 8 For COVID-19 the theory is that ivermectin binds to and destabilizes the Impα/β1 heterodimer, which is necessary for nuclear transport and preventing transport of a SARS-COV-2 cargo protein, which is thought to inhibit host viral infection response. 9 Thus, ivermectin is thought to enhance the bodies response to SARS-COV-2, by inhibiting SARS-COV-2’s inhibition of host viral defenses mainly in lung tissue. Essentially, even in the best-case scenario, and only looking at the lungs, we know SARS COV-2 impacts many other organ systems, that ivermectin is unlikely to ever reach theoretical potential therapeutic levels.

As of now we are still pending high quality randomized controlled trials, as noted on clinicaltrials.org and as referenced by the Cochrane Review. 1 So far one double blind randomized controlled trial for ivermectin in mild disease has been published in JAMA (Lopez-Medina et al 12 ) which shows no benefit to ivermectin over placebo. However, currently due to a large amount of disinformation and misinformation, many people are clutching to the idea of ivermectin saving the lives of their loved ones who are critically ill. Though we do not have an absolute number, some of these families, when their responsible doctors refuse to prescribe ivermetin, have gone to court. They sought the aid of a small number of physicians who are pro-ivermectin and several other medications and have managed to get court ordered injunctions requiring the administration of ivermectin. At present the majority of these cases appear to not actually attempt to rule on the medical indication of ivermectin, rather in the absence of time they have ordered injunctions requiring certain treatment to be provided until the court is able to actually rule on the merits. The best example is a case in Cincinnati, which was first hailed by these groups as a major success of the courts ordering physicians to give ivermectin, but has now recently had the injunction overturned, with the court ruling that they cannot compel the physicians to provide specific treatments. 13 This is far from the only case.

At present, most of the adverse events appear to be from people using veterinary ivermectin or topical preparations, both of which can have much higher drug concentrations, or simply be difficult for patients to accurately dose. So, one might say that from a harm reduction standpoint it is safer to prescribe a medication than force people to go to the vet, just like in Seinfeld, season eight, episode ten, where Kramer who does not have health insurance gets medications prescribed for a dog. However, in this case, the very act of physicians prescribing ivermectin legitimizes ivermectin as a treatment for COVID-19, which appears to be enabling individuals to forgo proven preventative measures, including vaccines and mask wearing. At the end of the day, more high quality randomized controlled trials are still forthcoming, but at present, there really is no good signal that it has benefit, and there are clear harms beyond just toxicity and adverse events.

References:

1. PoppM WS. Cochrane Library Cochrane Database of Systematic Reviews Ivermectin for preventing and treating COVID-19 (Review). 2021. doi:10.1002/14651858.CD015017.pub2

2. Roman YM, Burela PA, Pasupuleti V, Piscoya A, Vidal JE, Hernandez A V. Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials. Clin Infect Dis. 2021;101(Xx Xxxx):1-8. doi:10.1093/cid/ciab591

3. Bryant A, Lawrie TA, Dowswell T, 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(4):e434-e460. doi:10.1097/MJT.0000000000001402

4. HAN Archive - 00449 | Health Alert Network (HAN). https://emergency. cdc.gov/han/2021/han00449.asp. Accessed September 6, 2021.

5. ABEM Statement about ABEM-Certified Physicians Providing Misleading and Inaccurate Information to the Public. https://www.abem.org/public/ news-events/news/2021/08/27/abem-statement-about-abem-certifiedphysicians-providing-misleading-and-inaccurate-information-to-the-public. Accessed September 6, 2021.

6. ivermectin, scabies - Explore - Google Trends. https:// trends.google.com/trends/explore?date=2019-08-06 2021-09-06&geo=US&q=ivermectin,scabies. Accessed September 6, 2021.

7. FAQ: COVID-19 and Ivermectin Intended for Animals | FDA. https://www. fda.gov/animal-veterinary/product-safety-information/faq-covid-19-andivermectin-intended-animals. Accessed September 6, 2021.

8. El-Saber Batiha G, Alqahtani A, Ilesanmi OB, et al. pharmaceuticals Avermectin Derivatives, Pharmacokinetics, Therapeutic and Toxic Dosages, Mechanism of Action, and Their Biological Effects. 2020. doi:10.3390/ph13080196

9. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. 2020. doi:10.1016/j.antiviral.2020.104787

10. Guzzo CA, Furtek CI, Porras AG, et al. Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects. doi:10.1177/009127002237994

11. Lespine A, Alvinerie M, Sutra JF, Pors I, Chartier C. Influence of the route of administration on efficacy and tissue distribution of ivermectin in goat. Vet Parasitol. 2005;128(3-4):251-260. doi:10.1016/j.vetpar.2004.11.028

12. López-Medina E, López P, Hurtado IC, et al. Effect of Ivermectin on Time to Resolution of Symptoms among Adults with Mild COVID-19: A Randomized Clinical Trial. JAMA - J Am Med Assoc. 2021;325(14):1426- 1435. doi:10.1001/jama.2021.3071

13. Knight C. Judge rules hospital cannot be forced to give ivermectin. Cincinnati Enquirer. https://www.cincinnati.com/story/news/2021/09/06/ judge-rules-hospital-cannot-forced-give-ivermectin/5746518001/. Published September 6, 2021. Accessed September 6, 2021.