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Placebo-vs-Nocebo

Statin Intolerance: Placebo vs Nocebo

Last Updated: October 26, 2023 | Dr Reza Moazzeni

What is Nocebo and how it is different from Placebo?

To better understand the difference between Placebo vs Nocebo, Let’s start with a familiar scenario. You visited your doctor, and she was concerned about your blood pressure. You knew that you had a horrible day and probably was a one-off occasion, and believe if you rest, your blood pressure will normalise. You have read a lot about the side effects of the medications and have been trying to avoid them. The doctor eventually twists your arm and prescribes the medicine for you. You go home and read the pamphlet, which has listed numerous “likely” side effects. 

After a few days, you feel like you are experiencing many of these side effects, to the point that you stop the medication. Another person who doesn’t worry about side effects will take the same medicine with virtually no problems. Here a complex mental game is in play that stops you from adhering to potentially lifesaving treatment. Before diving further into the topic, let’s define some essential terms.

Terminology

Placebo:

A placebo is an inactive treatment or procedure designed to mimic a therapy but has no therapeutic effect. Mostly weakened sugars with no biological effect.

Nocebo:

A nocebo is a harmless medication, procedure or vaccine that causes harm due to a patient’s negative expectations or beliefs about it. 

Placebo Effect:

The placebo effect is when a person experiences improvement from a treatment due to their belief in its effectiveness, even if the treatment is inactive or neutral.

Nocebo Effect:

The nocebo effect is when negative expectations of a treatment lead to negative effects, even if the treatment is harmless. “Think sick, be sick.”

Where does the evidence stand?

Statins have proven to be vital medications in reducing the risk of Heart attack and ischemic heart disease, both in people with (secondary prevention) or without (primary prevention) known heart disease. Numerous studies have demonstrated the beneficial effects of statins in reducing mortality, notably in individuals with a history of heart disease. Here are some examples:

Heart Protection Study The Heart Protection Study involved over 20,000 participants and found that treatment with simvastatin reduced the risk of heart attacks, strokes, and other cardiovascular events.
The JUPITER trial The JUPITER trial involved over 17,000 participants with normal cholesterol levels but elevated levels of CRP, a marker of inflammation. The trial found that treatment with rosuvastatin reduced the risk of cardiovascular events.
The 4S study The 4S study involved over 4,000 participants with a history of heart disease and found that treatment with simvastatin reduced the risk of death from all causes and the risk of heart attacks and strokes.
The PROSPER study The PROSPER study involved over 5,000 participants aged 70 to 82 with a history of heart disease or high risk for cardiovascular diseases. The trial found that treatment with pravastatin reduced the risk of cardiovascular events.

Although there are cases of side effects from any medication, statins have proven to be highly efficacious – when indicated – with an excellent safety profile. New imaging techniques like Intra Vascular Ultrasound (IVUS) or Optical Coherence Tomography (OCT) have shown that reducing LDL with statins can reduce the size of the coronary plaques, i.e. reversing the atherosclerosis process. However, many patients hesitate to take these medications for various reasons, including muscle pain, memory loss or the fear of diabetes. There are many reasons for this “fear”, including negative media coverage over the years. 

However, contemporary evidence has shed more light on this complex issue. A well-done study, SAMSON Trial, showed that most patients who could not tolerate statins were likely experiencing the Nocebo effect. After patients realised their symptoms were also present when taking a placebo, most could restart statins without further side effects. 

Another study that shows the power of the Placebo effect is the ORBITA trial. This trial involved patients with significant coronary artery disease who were divided into two groups. One group had a coronary angiogram or angioplasty, and the other had a sham (fake) procedure. The patients in the second group thought that they had an actual procedure. Those who underwent a sham coronary angiogram had remarkable improvement in their symptoms, despite not having the actual procedure! They felt better because their mind BELIEVED they had an effective treatment, the Placebo effect.

There are many other examples of this sort in daily practice, including those with a diagnostic echocardiogram or stress echocardiogram. Although these are “diagnostic” tests, many patients feel better as they believe they had some “therapy, ” and their minds start healing.

How the mind can control the body and cause symptoms?

Despite years of investigation, there is yet to be a clear answer to this question. The mind controls the body through the central nervous system, i.e. brain and the spinal cord. The brain – the command centre – sends signals through the nervous system to control bodily functions.  The mind and body are closely interconnected, and our thoughts and emotions can significantly impact physical health.

For example, when we experience stress, our body releases adrenaline and cortisol, increasing heart rate and blood pressure with deleterious effects. In addition, the mind can also influence the body through the power of suggestion, where a person’s belief or disbelief in a treatment can lead to actual physical symptoms, even if the treatment is neutral. These symptoms are real and can be severe – at times disabling -and can significantly change people’s lives, for good or bad.

Changing a “cemented belief”, right or wrong, is highly challenging. If you strongly believe eating pork is unacceptable – for religious, medical or eco-conscious reasons – changing your belief would be highly unsuccessful. Or if you think vaccines are harmful and believe in conspiracy theories, you do all you can to avoid vaccination. You have convinced yourself that some specific therapy is harmful and should avoid it at all costs. If you vaccinate with that mindset, you will likely experience the side effects! This idea stems from deep beliefs – formed during life – and maybe past negative experiences, likely going back to childhood.  Your mind is “set” to experience side effects and, expects them; without them, it won’t be satisfied. 

The mind controls the body through a complex interplay of neural signalling, hormonal regulation, and psychological factors. In short, our mind is an extraordinary and robust machine that can affect our physical health immensely!

How does the Nocebo effect change patient views and outcomes?

While the Placebo effect can be positive and helpful, the Nocebo effect can endanger your life, for example, by refusing life-saving treatments. In medicine, the nocebo effect plays a significant role in communication. For example, before prescribing a medication, you may say, “This tablet may cause a headache.” With this comment, the patient’s likelihood of returning with a headache is high. However, rephrasing the sentence: “with this tablet, most people feel no pain at all, but an absolute minority (only one per cent) might experience headache” will lower the patient’s expectation of having a headache.

The mind-body connection is a complex and fascinating inter-relationship. Awareness regarding this intricate connection makes patients realize how their beliefs and thoughts can positively or negatively impact their health. As this is a mutual relationship, the reverse is also true. How we look after our physical health (by what we eat or how much we exercise) can also affect our mental well-being.

Accepting a medication or treatment depends on many factors, including patients' trust in their doctor, past experiences with the same therapy, and how the doctor presents information regarding the therapy. Due to ethical obligations and full-disclosure laws, a doctor has to provide the data. However, the way this information is presented can make a significant difference to the outcomes.

Placebo vs Nocebo Dr Moazzeni
Placebo vs Nocebo - SAMSON Trial

Conclusion:

Our brain is hard-wired to win. Our mind is a powerful machine that pushes us subconsciously towards our goals – good or evil – as long as they are “goals”. This dynamic plays a role in all aspects of our lives, including health, relationship, career, fitness and everything else.

In the case of Nocebo, our goal is to prove that we were right and that some treatment, medication or vaccine wasn’t good for us. Our mind plays all sorts of tricks to win the argument, even at the expense of our health. On the other hand, if our brain decides “something is good for us”, we would be eager to try that and will physically feel good even without any objective proof. That’s what Placebo is.

Placebo and nocebo effects are powerful and extremely common in daily life and medicine. Neurobiological mechanisms, information – or misinformation – about a drug, patient expectations, and previous drug or procedure encounters can generate these effects. 

Increased awareness about Placebo and Nocebo helps to adopt strategies to promote the placebo effects and minimize the nocebo effects. This simple fact can improve outcomes and minimize unwanted symptoms in daily clinical practice.

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