April 1, 2021

Placebo Effect vs. Placebo Response: Is There A Difference?

Placebo effect and placebo response are often used interchangeably – despite being two different phenomena. In this blog, we highlight the differences—and why it matters.  

Placebos are an important part of clinical research. But the impact of placebo use is a long-discussed matter in the biotech and pharmaceutical industry. While helpful in determining drug efficacy, certain factors make using placebos as drug comparators rather complicated.  

Most will say placebo treatment results in the placebo effect. But there’s also the placebo response—a related yet separate phenomenon. To understand the difference, let’s first look at how placebos work in a clinical trial. 

How Do Placebos Work 

A placebo, which is an inactive sugar pill in most cases, is administered to mimic a drug or therapeutic being tested. The placebo has no real impact on the condition that the experimental drug is designed to treat.  

Because of this, placebos are commonly used as a control in randomized trials, in which one group receives the experimental drug and the other receives the placebo. If both groups have a similar reaction, whether there’s improvement or not, this means the experimental drug does not have better efficacy over the placebo. If the clinical trial statistician can indicate that the active drug has better efficacy over the placebo with an acceptable safety profile, then the drug may move to the next stage in the study (and it has a better chance of approval).  

On paper, this process seems simple—but it’s actually more complex. 

This is because, when a patient takes a treatment (inactive or active), there are numerous factors at play beyond the placebo effect that can cause clinical improvement – making it difficult to measure true drug efficacy. Next, we will analyze those factors by comparing placebo effect vs. placebo response.  

Placebo Effect vs. Placebo Response 

The placebo effect is a biopsychological phenomenon that occurs in many clinical trial patients as a product of their response to a placebo. The placebo effect may produce a real and beneficial, neurobiological event, inducing a change – or perception of a change –  in a patient’s symptoms.   

The placebo response is the measured improvement of a patient in a clinical trial after receiving a sham treatment.  

What’s the Difference? Placebo Effect vs. Placebo Response 

By definition, the placebo effect is something real that happens in a patient’s brain, whereas the placebo response is what clinical trials actually measure when comparing placebo groups to active groups. In other words, the placebo effect is one factor, while the placebo response is a combination of a few different factors that may mimic clinical improvement.  

The placebo effect and response are related because the effect is actually one piece of the response. Each patient in a clinical trial will have a placebo response that is unique to them, influenced by their own individual characteristics. These include:  

  1. Contextual Factors 

Social interactions and subtle contextual cues may increase a patient’s probability of exhibiting placebo response. 

For example, a positive physician-patient relationship can impact a patient’s perception of the level of care they are receiving in a study and heighten expectations for positive results.   

  1. Geography & Culture 

Certain cultures across the world have a varying tolerance of symptoms, which creates variations in the intensity of symptom reporting.  

Take pain as an example.  

Some cultures have higher pain tolerances. So, a patient may report feeling less pain after taking medication because they genuinely don’t feel as much pain.  

But a less tolerant patient from somewhere else may not report the same positive results. This translates to varying degrees of placebo responsiveness, because one patient experiences clinical improvement while the other doesn’t, simply due to their cultural and individual pain tolerances.  

  1. Demographics 

Similarly, different age groups, genders and other demographics also report symptoms differently and respond to treatments with varying expectations. 

  1. Placebo Effect 

Lastly, there’s the placebo effect itself. When a patient takes a drug, there’s a chance that, in addition to the other factors listed above, they will have a placebo effect.  

The first four factors are more straightforward to trace. But where does this placebo effect come from?  

The precise causes of the placebo effect are still being understood, but it’s largely attributed to a few different psychological and neurobiological factors.  

For example, the act of physically taking a pill may elicit a positive response, even with a placebo treatment, because the patient associates taking medicine with feeling better.  

Also, patients who experience the placebo effect have been found to have increased levels of “feel good” neurotransmitters. The placebo effect actually impacts the same areas of the brain that real treatments for conditions like chronic pain activate. This effect leads to real clinical improvement but not due to the active treatment.  

Even though this clinical improvement is a positive thing, the placebo response makes it more difficult to measure if the experimental drug itself is actually working or not.  

Why It Matters 

Why does understanding placebo effect vs. placebo response matter?  

It’s tempting to try to eliminate the placebo effect, as some clinical trials try to do by creating placebo lead-in phases and removing high responders from the main phase of the study. Removing individuals who demonstrate a placebo effect creates other problems, most notability decreasing the translatability of data to the general population. This is because the placebo effect is a natural phenomenon that people everywhere will experience to a varying degree. 

But the good news is you can predict placebo response. Because placebo response also i includes placebo effect, you can predict the placebo response and, in doing so, will naturally address placebo  effect.   

And to do this, you have to understand patient psychology. Because, as discussed, placebo response is related to unique patient characteristics. Most components of placebo response either originates from a patient’s psyche (placebo effect) or influences a patient’s psyche (contextual factors).  

Conclusion: Predict Placebo Response 

In order for clinical trials to move to the next stage or drug approval, the statistician has to indicate that the active drug has better efficacy over the placebo with an acceptable safety profile. But this is difficult when there are many sources of data variability, or noise.  

While other sources can be accounted for, the placebo response has been a historically challenging source of noise. This is because most efforts to mitigate placebo response have been related to study design and trial conduct. But characterization of the placebo response can – and should – be included in the statistical analysis – not to try to remove the placebo response, but to remove the data variability associated with it.  

How do you actually do this?   

This can be accomplished by combining baseline patient data (including psychological traits, demographics, and other inputs) using a pre-defined machine learning-based algorithm, you can calculate a score that represents each patient’s predicted level of placebo responsiveness. Trial statisticians can then use this score as a covariate to better analyze clinical trial data, reduce the noise related to placebo response, and increase overall trial power.  

Placebell©™ is a proven solution that helps clinical trials accomplish this by leveraging our validated questionnaire and proprietary algorithm. 

Learn how Placebell©™ can help you account for the placebo response in clinical trials. Get in touch today.

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