Ep 136: A 71-Year-Old Man with Prostate Cancer
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This is Katarina Heidhausen, Executive Editor of Harrison's Principles of Internal Medicine. Harrison's Pod Class is brought to you by McGraw-Hills Access Medicine, the online medical resource that delivers the latest content from the best minds in medicine. And now, on to the episode. Hi, everyone. Welcome back to Harrison's Pod Class. We're your co-hosts. I'm Dr. Kathy Handy. And I'm Dr. Charlie Wiener, and we're joining you from the Johns Hopkins School of Medicine.

Welcome to episode 136, a 71-year-old with prostate cancer. Hey, Kathy. Today we're hitting very close to home as you are an active clinical investigator. Now I'm curious. Okay, here's our question. You are enrolling a 71-year-old patient into your prostate cancer clinical trial. It's a placebo-controlled trial of a new medication designed to control GI side effects of ongoing treatment.

All of the following statements regarding the placebo effect are true, except... Let me just interrupt you briefly before you give the options. This is a really important consideration in clinical trials, and as you mentioned, is near and dear to my heart because this is what I do. Placebo-controlled trials are often hard to do because both patients and clinicians often have difficulty maintaining clinical equipoise.

With so much information out there, it's often the case that patients are less willing to consent to placebo-controlled trials, plus it has impact on informed consent, statistical analysis of outcomes and side effects, and even understanding the difference between a statistically relevant versus a clinically relevant outcome.

And as a fun historical note, in 1784, Ben Franklin, with some colleagues in France, conducted one of the first placebo-controlled trials to debunk the efficacy of the highly popular mesmerism treatment. Ben Franklin was an OG.

How do you utilize placebo controls as a clinical trialist, though? In randomized placebo-controlled clinical trials, the effect of the drug is calculated by simply subtracting the outcomes in the placebo treatment arm or placebo response from the drug response. This does four things. One, it controls for placebo effects.

Two, it controls for changes in the outcome of interest due to natural history, such as the tendency for a common cold to resolve on its own in 7 to 10 days. Three, it controls for regression to the mean, where extreme baseline measures tend to move toward the group mean. And lastly, it controls for the Hawthorne effects, which describes the tendency for people to change behaviors when being observed.

This is why placebo-controlled trials are considered the gold standard for a clinical trial. As usual, you're on point and anticipating some of the question. I'll start again. The question asks, all the following statements regarding placebo effect are true, except one option is going to be wrong. Option A is administration of a placebo or inactive treatments can have significant therapeutic benefits. Option B, naloxone can exacerbate placebo effects in the experience of pain.

Option C is neuroimaging studies have identified consistent changes in the brain in response to placebo treatments. Option D is over 25 genes have been associated with the placebo response in genome-wide association studies or GWAS studies. And option E is placebo effects are related to include the patient's expectation and conscious or subconscious conditioning.

What a fun question, Charlie. So first, there is no doubt that placebo or quote-unquote inactive treatments can have significant therapeutic effects. I'll also add that placebo treatments can also have notable side effects. These effects are called nocebo effects, which is meant to describe production of negative effects from negative verbal suggestions, contextual cues, or associative learning.

In clinical trials, on average, 25% of participants randomized to placebo report side effects, and some studies show that the rates of side effects do not significantly differ between the active drug and placebo. Okay, so A is true, and it sounds like E is also true. Yes, placebo effects are clearly related to include the patient's expectation in conscious or subconscious conditioning.

Psychological studies demonstrated that expectations are shaped by factors intrinsic to the patient, including their past experiences and core beliefs or mindsets, and extrinsic factors, including environmental cues, clinical practice, and information received about a treatment. Things like the presence of a clinician wearing a white coat, how the clinician frames the discussion regarding the intervention, performance of a physical examination, and prior experiences all can impact the magnitude of the placebo effect.

Furthermore, neuroimaging studies have identified consistent changes in the brain in response to placebo treatment that suggests that placebo effects work by integrating incoming information about extrinsic factors with prior experience and mindsets to update expectations of treatment benefit.

Also, functional MRI has also been used to create brain signaling profiles that are predictive of placebo responders. In a study of patients with chronic osteoarthritis pain, right midfrontal gyrus connectivity effectively identified placebo pill responders. Okay, wow, that's pretty cool. Okay, so C and E are also true. We're narrowing it down.

You mentioned trying to identify profiles of placebo responders. Option D mentions looking for gene profiles by GWAS. What's the story there? Yeah, GWAS of the placebo control arms of clinical trials have found a number of genetic associations, mainly in the dopamine, opioid, and serotonin signaling or receptor pathways. To date, there are 29 genes associated with response to placebo in the GWAS catalog. Okay, so D is true.

So that means that option B, which talks about naloxone, is false. Yes, the false statement is B. In fact, as far back as the 1970s, there was pharmacological evidence demonstrating that the opioid antagonist naloxone could abrogate placebo effects in the experience of pain after molar tooth extraction. These studies laid the groundwork for demonstrating that psychological forces could affect patient physiology.

Early neuroimaging studies revealed the release of endogenous opioids and dopamine signaling proportionate to the expectation and perception of how well a given placebo intervention worked. And as I mentioned before, some of the genes implicated in the placebo response were in the opioid signaling pathway. Okay, so the teaching point in this question is that both the placebo and the nocebo responses are real, and the interaction between the psychological and physiologic factors determine these responses.

Understanding these responses and their mechanism is important for designing, analyzing, and interpreting clinical studies, and they have potential therapeutic implications in the care of your patients.

If you liked this episode, you can find this question and others like it on Harrison Self-Review, and you can read more about it on the chapter on placebo and nocebo effects. Visit the show notes for links to helpful resources, including related chapters and review questions from Harrison's, available exclusively on Access Medicine. If you enjoyed this episode, please leave us a review so we can reach more listeners just like you. Thanks so much for listening.