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The mind-body connection in Covid-19

The ability of placebos – or what have sometimes been called “dummy pills” – to trigger physiological responses that help people battle Covid-19 are now being reported by scientific researchers.

These revelations as to a “placebo effect” response to the world’s newest infectious disease follow on earlier reports of a nocebo effect – the opposite of a placebo effect – widely blamed for medical issues some people reported after being given Covid-19 vaccines and a more controversial report of nocebo effects leading some to suffer from what has come to be called “long Covid” despite blood tests indicating they had never been infected with the Covid-19-causing SARS-Cov-2 virus.

There is so much still unknown about how exactly the human organism functions. Historically, the placebo effect itself has been known for decades, but has generally been linked to treatments for pain.

After completing “a systematic review and network meta-analysis” of  33 random-controlled trials (RCTs) of Covid-19 drug treatments, however, a collective of 19 researchers from universities in the United Kingdom, Taiwan and Australia, reported finding “a significantly lower risk of all-cause mortality in patients with Covid-19 treated with (a normal) standard of care (SoC) plus placebo compared with those treated with SoC alone, suggesting a placebo effect.”

Their little-noticed study was published in the peer-reviewed journal Psychiatry and Clinical Neurosciences at the end of last year. It was primarily designed to examine the “inconsistent results” of studies of tocilizumab and sarilumab, two so-called “interleukin 6 antagonists” prescribed to report the much-discussed “cytokine storms” killing many Covid-19 patients early in the pandemic.

But the study does raise interesting questions about the decisions of some doctors to prescribe ivermectin, hydroxychloroquine or chloroquine early in the pandemic when few drugs were known to work to treat Covid-19

Surprising result

A placebo effect influencing physiological responses to an infectious disease is even harder to explain than how a placebo might alter perceptions of pain, given that pain tolerances among humans are highly variable.

Treatments for pain led to the first documentation of what would come to be called the “placebo effect.” The word placebo itself has an interesting history.

It traces back to the early Catholic Church where it was used to describe mourners paid to show up at funerals, or there in hopes of obtaining a free meal, as “singers of placebos,” according to information compiled by researchers at the Medical University of Vienna.

They documented a physician in the late 1700s using what he called a placebo to “comfort and please patients, whenever he was not sure of his technical ability or knowledge to help them,” but “in this context the definition of placebo was not the actual substance, but his intention for the prescription itself.”

In 1785, the word placebo first appeared in a dictionary where it was defined as “a commonplace method of medicine.” By the 19th Century, however, the definition had been altered to describe a placebo as “an epithet given to any medicine adapted more to please than benefit the patient.”

This definition would change significantly after World War II from which there emerged a story about the late Dr. Henry Beecher, a Harvard-trained doctor, injecting soldiers with benign solutions of saline after running out of pain-killing supplies of morphine, and later reporting that 40 to 90 percent of the soldiers responded to the salt water as if it were a drug.

This story of discovery has since been questioned, but there is no doubt Beecher returned home from the war intrigued by the “placebo effect.” In 1955, he authored an article for the Journal of the American Medical Association (now just JAMA) titled “The Powerful Placebo.”

Beecher therein claimed that in 15 trials with different diseases, 35 percent of 1,082 patients were satisfactorily treated with a placebo, a claim that has also come under fire in modern times.

A pair of German researchers who reviewed Beecher’s work for the peer-reviewed Journal of Clinical Epidemiology in 1997 reported that “no evidence was found of any placebo effect in any of the studies cited by him. There were many other factors that could account for the reported improvements in patients in these trials, but most likely there was no placebo effect whatsoever.”

Nonetheless, there is now a fairly universal belief that the placebo effect and the nocebo effect, which some have described as the placebo’s “evil twin,” do exist. Lacking a nocebe effect, how could anyone account for all those side effects reported by those vaccinated against Covid-19?

“Today,” the University of Vienna researchers wrote in 2020, “the placebo effect is still a hot scientific research and clinical topic. It is used as a control arm in randomized controlled trials to quantitatively distinguish the effect of the active agent from that of placebo in order to determine the true pharmacological effect. The drug has to prove its effectiveness and adverse event profile compared to placebo for approval by regulatory agencies.”

That is a valid standard for regulations, but what is left hanging is the ethical question for physicians in situations – such as that which existed with Covid-19 at the start – wherein otherwise harmless drugs might have some benefits as placebos even if data is lacking to prove the “truly” work.

Big controversy

Enter the anti-parisite drug Ivermectin flagged as an effective treatment early in the latest pandemic. A small study conducted in Bangladesh in the fall of 2020 concluded that “a five-day course of Ivermectin was found to be safe and effective in treating adult patients with mild Covid-19.”

The drug, however, quickly became highly controversial when other studies questioned that study’s accuracy.

NBC in August 2021 reported a huge demand “for Ivermectin, a drug primarily used to deworm animals that has become the latest false cure for Covid-19” and blamed “the organization America’s Frontline Doctors, whose founder stormed the U.S. Capitol on Jan. 6, (and) has become well-known in the Facebook groups and Reddit communities where anti-vaccination sentiment thrives.”

Ivermectin would eventually be ruled out as an effective treatment not because it had no effect but because there was no evidence the effect it did have was any greater than that of a placebo.

The drug’s effectiveness was still being debated as late as last year when researchers reporting in the journal BMC Infectious Diseases wrote that “evidence on Ivermectin as a treatment for Covid-19 is controversial. A Cochrane review concluded that the efficacy and safety of Ivermectin is uncertain (evidence up to April 2022) and WHO recommended its use only in the setting of clinical trials.”

That study found that “although ivermectin resulted in statistically significant lower viral load in patients with mild to moderate Covid-19, it had no significant effect on clinical symptoms.”

By the time that study came out, however, Yakima, Wash., Dr. Richard Wilkinson had already been fined $15,000, ordered to submit to a “clinical competency assessment,” and placed on probation for five years for prescribing the drug to “seven patients for COVID-19 infections without documenting a sufficient rationale for prescribing the medication and without informing the patients that the medication is not FDA-approved to prevent or treat Covid-19,” according to the Washington Medical Commission.

He was one of three Washington-state doctors so charged, and a fourth claimed she “relinquished her state medical license under duress after her employer, Washington State University, warned her that she would be reported to the commission for her public
comments against vaccinating children to prevent Covid-19,” according to an article in the British Medical Journal (BMJ) reporting that all four were suing the Washington Commission.

There was never any statistical evidence children needed the drug. The disease posed a risk to children already suffering from chronic illnesses, but the death rate among healthy children was tiny.

And in some of the cases where Ivermectin was involved, it was prescribed because patients or their families demanded it – there being no other treatments well-defined as successful early in the pandemic.

One of the doctors charged in Washington, Guito C. Wingfield, defended himself by arguing that he had “relied on his 35 years of experience in internal medicine in his treatment of the patients” and the fact that “none of his patients suffered harm and not one of the patients he treated filed any complaints against him,” according to a story in The Chronicle, a Centralia, Wash. publication.

Bigger blow up

The dispute over Ivermectin, however, paled compared to that revolving around hydroxychloroquine, a drug long used to treat malaria and some autoimmune diseases such as systemic lupus.

With the pandemic erupting near the end of President Donald Trump’s first term in office, he endorsed the use of hydroxychloroquine and sent the media and some doctors into a tizzy. At the time, there were some suggestions the generally harmless drug might be effective.

“Hydroxychloroquine (HCQ) has shown efficacy against coronavirus disease 2019 (Covid19) in some but not all studies,” a pair of Illinois doctors reported in the journal New Microbes and New Infections in November 2020.

Citing what was essentially a literature search, they reported that “HCQ was found to be consistently effective against Covid-19 when provided early in the outpatient setting. It was also found to be overall effective in inpatient studies. No unbiased study found worse outcomes with HCQ use. No mortality or serious safety adverse events were found. HCQ is consistently effective against COVID-19 when provided early in the outpatient setting, it is overall effective against COVID-19, it has not produced worsening of disease and it is safe.”

When Trump hyped earlier and similar reports as to the effectiveness of the medication, demand for the drug skyrocketed and a Phoenix man died and poisoned his wife, who survived, after apparenlty trying to home-brew hydroxychloroquine.

“Arizona man dies after attempting to take Trump coronavirus ‘cure,'” The Guardian, a highly progressive newspaper headlined above a story that said “a Phoenix-area man has died and his wife was in critical condition after the couple took chloroquine phosphate, an additive used to clean fish tanks that is also found in an anti-malaria medication touted by Donald Trump as a treatment for Covid-19.”

Further down in the story, the man’s wife was quoted saying “Don’t take anything. Don’t believe anything. Don’t believe anything that the president says and his people … call your doctor.”

That quote was rather strangely followed by a paragraph reporting that it was “unclear if the couple took chloroquine phosphate specifically because of Covid-19, the disease caused by the coronavirus.”

None of that, however, mattered in a country in which the blusterous statements of the then-president had become fodder for a mainstream media intent how helping to get him voted out of office.

Doctors were left to figure out for themselves what to do, which put some in a difficult spot.

With no proven drugs for treating a new disease, and patients demanding a relatively benign drug that might work, what would you do? You could give them sugar pills and tell them it was the drug or drugs they wanted, but such a lie would be a clear ethical violation.

So what does one do when these placebo issues enter the picture? It’s an interesting question.