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Understanding drug responses is key for both doctors and patients

I have often been quoted as saying, “One cannot have bad skin and good health.” Skin merely reflects what lies beneath.

I was born in England, and my parents went to India to work in medical mission hospitals, and I studied medicine (and later surgery) in India before heading overseas. Given the abundance of topical disease and lower socioeconomic populations, hospital-based training in India hones your clinical skills more than in the West where we become better at reading scans as opposed to using our eyes and hands to make diagnoses. A rheumatic heart disease-ridden ward, bristling with murmurs—both systolic and diastolic—also teaches physicians the limits of what “treatment” can mean. When we were “on duty” as house officers, the entire team—including consultants—would stay overnight, bringing to life the art of reading medicine’s social X-rays—where signs and symptoms blend with unspoken rules, not-so-secret crushes, and silent shrewdness. I remember a senior doctor asking me to examine the hands of a patient at night and pointing out Osler’s nodes –-painful, red, raised lesions on the hands that had been caused by subacute infective endocarditis due to rheumatic fever. These lesions had first been described by William Osler, the Canadian physician, one of the founders of the Johns Hopkins University School of Medicine and the pioneer of residency programmes for medical graduates, to hone their clinical skills.

In the West, a consultant staying overnight with his students would be as unthinkable as the Pope rethinking his choice of religion. It was, however, as Osler would have it. Osler had introduced a full-time, sleep-in residency system whereby staff physicians stayed in hospital building, a practice that somehow had survived at my medical school until I finished my medical education.

“The desire to take medicine is perhaps the greatest feature which distinguishes man from animals,” remains one of Osler’s most famous quotes (1). But in the same public lecture, he had followed up this sentence with a lesser known one indicating that our obsession with pharmaceuticals may not be inherently healthy (2): “Why this appetite should have developed, how it could have grown to its present dimensions, what it will ultimately reach, are interesting problems in psychology.”

As someone who trained in family medicine and worked as a generalist before specialising in skin, and someone who writes fiction and non-fiction, the philosophy of medical science interests me. What I have found—in discussions with medical colleagues in peer-groups—is that medical practitioners subliminally view drugs as being far more effective than they really are. It is almost an unconscious belief, an innate optimism in one’s own dictates while writing out prescriptions that leads to doctors’ subconscious credence that patients’ respond to drugs and none to placebo, but we know neither of these is true. It may be that because medicine is becoming so specialized, doctors have no time, or interest, to research effectiveness of medications outside their specialty. 

In this article I shall give you some examples. The problem with understanding the true efficacy of medicines is that they may actually do what they are supposed to do, but the real outcome for the patient may be less than the metrics. For example, we know a medication may reduce blood pressure or blood sugar, but the real test is in knowing the absolute risk or response difference (ARD) when compared with placebo. To illustrate further, if 45% of patients respond to a drug and 30% to a placebo, then the ARD is 15%.

What made me think of this topic was the realization that more than half of those aged over 60 whom I examined for skin cancers last week were on aspirin or statins—the ubiquitous cholesterol-lowering medications. I routinely ask people if they are on any medications, as some common medications increase skin cancer risk (but that topic is for another day). When I quizzed them if they had had cardiac events or stokes, it seemed the majority were on aspirin or statins for prevention. That makes some sense from a pharmaceutical model of health. After all, weren’t governments considering polypills—containing aspirin and a statin, or statins and blood pressure lowering pills, as a panacea for everyone a few years ago?

Let’s look at the ARD for aspirin. A major review suggested that the difference in ARD between aspirin and placebo for primary prevention of cardiovascular events is only 0.07 % per year. A very recent article in the prestigious JAMA noted the fact that when it came to aspirin as a preventer, the number needed to treat to prevent a single cardiovascular event was comparable to the number needed to harm by causing one major bleeding event!

There is no doubt that statins lower cholesterol. In fact, they lower cholesterol by 30%, a very significant effect. But of how much use is a statin as a preventer to prevent death? If one looks at reports of cardiovascular events and mortality, the effects are smaller—the ARD between statins and placebo is 4 % for cardiovascular events and 1.2 % for mortality within 5 years. Hardly dramatic. Of course, if one studies this effect for a period longer then 5 years, the effect may be greater (or lesser). 

Another review from the influential Cochrane Library on the effectiveness of paracetamol, a medication widely recommended for knee and hip arthritic pain noted: “Paracetamol (acetaminophen) is vastly recommended as the first‐line analgesic for osteoarthritis of the hip or knee … At 3 weeks to 3 months follow-up, there was high–quality evidence that paracetamol provided no clinically important improvements in pain and physical function.”

I am not advocating anyone stopping these (or any) medications without discussions with their own doctors. The point I am making is, our human preference for black or white over shades of grey may sometimes offer a false sense of clarity. Do you and your doctor discuss the ARD of the medications you have been prescribed, or the interactions between different drugs that may cause considerable harm?

Amos Tversky and Daniel Kahneman, two friends and notable psychologists—the latter better known for his books on economics and decision-making—have spent decades studying cognitive bias. In a famous experiment on explaining a surgical treatment option, they told one group of doctors that a patient had a 90% chance of surviving the surgical procedure. The other group was told the patient had a 10% chance of dying from the surgical procedure. While both these scenarios were in fact identical, what happened was that doctors in the first group were nearly twice as likely to recommend surgery! 

In The Undoing Project, Michael Lewis writes about such “nudges in the medical world” that may be commonplace due to human biases. Your doctor may mean well, but a subconscious bias may result when nudged by a friendly, well-trained pharmaceutical rep or after a talk from a local specialist sponsored by a drug company. As an article in the Journal of the Royal Society noted: “Doctors are not creatures of fact… our decisions are influenced by a myriad of biases – both consciously and subconsciously tweaking everything we do.”

In my own practice, I tend to be a compulsive researcher, partly because of my strongly held philosophical view that I must treat every patient as I would treat myself or my family. I never recommend something I will not take, which is not to say I am infallible. As someone who has studied law, I am also asked to review cases that result from medical errors and provide independent medical advice. I learn a lot myself from these reviews of case reports, even if such an education is sadly facilitated by unwitting medical errors. But what I have learnt is that effectiveness of medical treatments can be distorted beyond recognition by our human biases that show that the same things can end up being both real and imagined.

(1) The Life of Sir William Osler (1925) Vol. II, p. 342.
(2) Would Osler stand by his famous quote today?
https://www.mcgill.ca/oss/article/controversial-science-health-history-news/would-osler-stand-his-famous-quote-today accessed 30 Dec 2022