The nocebo Effect
Because it is not just a positive expectation…
What induced the placebo effect in clinical trials?, Is there a component of the placebo effect in the actual experimental arm?…. why is the placebo effect not investigated with more detail in clinical trials, and even worse why using a placebo control group even when regulators and the scientific comunity are aware that “substantial responses are typically seen in placebo groups”, specially “in antidepressant trials, and these are often larger than the experimental treatment effect”.
Even in the “Major Depressive Disorder: Developing Drugs for Treatment Guidance for Industry – June 2018” it is mentioned: “For that reason, trials of effective antidepressants have a high failure rate (about 50 percent). Therefore, it is not possible to identify a consistent drug effect that could be used as a noninferiority margin in comparative trials. A placebo group is necessary to ensure that observed effects are not the result of spontaneous improvement, expectation bias, attention from health care professionals involved in the trial, regression to the mean, or other factors not related to the activity of the study drug. Source: https://www.fda.gov/media/113988/download
If the placebo effect is assumed to be associated with “spontaneous improvement, expectation bias, attention from health care professionals involved in the trial, regression to the mean, or other factors not related to the mechanism of action associated with the experimental treatment” then the same impact should be reflected in the experimental treatment itself.
In this blog, I aim to debate this topic and to explore the opposite complement to the “placebo effect”, but before we continue let’s clarify some definitions:
The placebo effect – Definition:
Early 13c., name given to the rite of Vespers of the Office of the Dead, so called from the opening of the first antiphon, “I will please the Lord in the land of the living” (Psalms cxiv.9), from Latin placebo “I shall please, ” future indicative of placere “to please” (see please). Medical sense is first recorded 1785, “a medicine given more to please than to benefit the patient. ” Placebo effect attested from 1900.]
Some additional definitions – Webmd.com:
A measure designed merely to calm or please someone.
A substance that has no therapeutic effect, used as a control in testing new drugs.
A biomedically inert substance given in such a manner to produce relief is known as a placebo.
A usually pharmacologically inert preparation prescribed more for the mental relief of the patient than for its actual effect on a disorder
An inert or innocuous substance used especially in controlled experiments testing the efficacy of another substance (such as a drug)
The first-person singular of the future tense of the Latin “placere” – to please – thus the placebo effect is a manifestation of the patient’s attempt to please the clinician.
Anything that seems to be a “real” medical treatment — but isn’t.
The effect of the simulation of treatment that occurs due to a participants’ belief or expectation that a treatment is effective
A placebo is a “dummy” treatment that appears as identical as possible to the test treatment with respect to physical characteristics such as color, weight, taste and smell, but that does not contain the test drug. (ICH E10)
But keep in mind that not all patients attempt to please the clinician, some of them may try to displease them or just have a negative expectation about the treatment – regardless of the actual active or inactive ingredients/components. There is even a significant group of participants known as “professional patients” or “frequent flyers”, there is also sites known for manufacturing data, so how this issue impact clinical trials and how we should analyze this issue… a question that I plan to respond later.
The nocebo Effect
A nocebo effect is said to occur when negative expectations of the patient/study participant regarding a treatment cause the treatment to have a more negative effect than it otherwise would have. For example, when a patient anticipates a side effect of a medication, they can suffer that effect even if the “medcation” is actually an inert substance. The complementary concept, the placebo effect, is said to occur when positive expectations improve an outcome. Both placebo and nocebo effects are presumably psychogenic, but they can induce measurable changes in the body.
So the CEBO EFFECT is the induced effect in the proportion of the effect size induced by the study participant’s expectation about the investigation medical product.
What induce the CEBO effect (placebo or nocebo)? Two factors: intrinsic and extrinsic issues associated with the patient/study participant and his/her environtment. Like in pharmacokinetics and pharmacodymics (what the drugs does to the body and the body does to the drug) here the CEBO effect is what the “brain does to the body and the drug”:
Intrinsic Factors:
Neurobiological
Psychological, and Cognitive factors
Pavlovian Conditioning
Hawthorne Effect (experimental subordination)
Natural disease progression
Regression to the mean
Disease status at baseline
Extrinsic Factors
Environmental
Methodologies for quantifying placebo effects
Potential impact of these effects on active treatment effects
Background medication
Social interaction
