Almost everyone has heard of the placebo effect, which consists of feeling the beneficial effects of an inert drug. But few know its flip side, “the nocebo effect”. In this case, people who take a drug, whether it is a placebo or not, experience unwanted negative effects. Here are the basics of the nocebo effect and what could be done to minimize its impact on treatments.
All drug trials should have a control group. People in this group are given an inert substance, also called a placebo – a “fake” medicine that does not contain any active ingredient. If the trial is for a specific pill, the control group will receive a pill that looks the same but contains no active ingredient. If it is to test a vaccine, the control group will receive a placebo injection.
However, there is a curious phenomenon that people taking placebos sometimes notice changes consistent with this that they are waiting for. Thus, many of them will see an improvement in their symptoms, which is called the placebo effect. Others, on the other hand, will notice the side effects that can be expected from the drug being tested, and they can be unpleasant. This is called the nocebo effect. The phenomenon of the appearance of expected undesirable symptoms but without a real cause was identified in 1961 by Walter P. Kennedy. The term derives from the Latin word “nocere”, which means “to harm”, and was first used to describe adverse effects caused by a placebo.
One study defined the effect nocebo as: unpleasant or undesirable results triggered by the context of the treatment, beyond any pharmacological effect inherent in the treatment itself. Thus, the simple fact of taking a tablet or having an injection can cause side effects, which are not due to the medicine it contains. And it can happen to those who take prescribed medications, and not just in trials.
Causes of the nocebo effect
If the drug itself is not responsible for the side effects, why are they happening? The need for health professionals to obtain informed consent could partly explain the nocebo effect. People undergoing medical treatment must give their informed consent for this treatment. To obtain informed consent from a patient or trial participant, physicians must fully explain the risks and benefits of treatment, including possible side effects. One study has suggested that when trial participants are told about side effects, they are likely to experience them whether or not they take the active drug.
So can negative expectations produce negative results? That may well be the case. A recent review of COVID-19 vaccine trials illustrates this point. Researchers who analyzed data from 12 trials found that 35% of people who received placebo injections experienced systemic effects, effects felt in areas of the body other than the treatment site, such as headaches and fatigue, after the first dose.
This figure was 35% for people who received the real vaccine. Therefore, the authors of this study suggest that approximately 76% of adverse events reported by people who received the real vaccine were nocebo events. In other words, they were not caused by the vaccine but by the expectations of the participants.
Physical or mental causes?
These symptoms felt are probably real, so if they are not due to the active treatment, what could be the cause? Experts have attributed the nocebo effect to both psychological and neurobiological causes. Many factors come into play. For example, previous negative experiences with the healthcare system and related treatments. If you have been dealing with complex health stressors and difficult treatment, you can expect more difficulty with additional treatments. We have evolved to anticipate results and avoid damage. From a psychological point of view, negative expectations may be fulfilled. If a patient hears that a treatment can cause drowsiness, and then feels drowsy, they will blame the drowsiness on the treatment.
In addition, people who have negative expectations about side effects may be more aware of symptoms and therefore more likely to report them. And studies have shown that people with anxiety and depression are also more likely to experience the nocebo effect.
Conditioning and past experience
Another explanation may lie in the packaging. The color of the tablets is a good example. A study by 1996 found that people associate red, yellow or orange tablets with stimulating effects and blue or green tablets with sedative effects. The researchers gave otherwise identical blue tablets to one group and pink tablets to the other. The group that took the blue tablets reported greater drowsiness.
And those who experienced adverse drug reactions in the past are more likely to experience them. report after re-treatment.
Part of the nocebo effect that results from neurobiology is nocebo hyperalgesia where the expectation of pain increases the pain experienced. When a person anticipates pain, they release cholecystokinin which allows the transmission of pain. If this anticipation and anxiety can be reduced, pain will also be reduced.
Sensations can be amplified by our brain in fear-triggered feedback loops , resulting in increased pain and other symptoms. This does not mean that the pain is not real, but rather that the pain mainly signals fear rather than harm.
Real effects on treatments
The real risk with the nocebo effect is when it affects treatments or drug trials. If a person attributes negative side effects to an effective treatment, they risk stopping that treatment, thereby losing the benefits along with the side effects. Over-reporting of side effects in a drug trial may mean that the drug is not licensed. This can have a real impact on health outcomes.
The nocebo effect can also increase these reported side effects and lead to negative health outcomes.
Some studies have suggested that reducing information about side effects may reduce the nocebo effect, but this raises ethical issues.
How to minimize the nocebo effect
Because the nocebo effect can negatively affect drug trials and alter the health outcomes of people taking medication, it is important to recognize it and determine how to assess and correct it in the study. Research has shown that boosting the placebo effect can reduce the nocebo effect. Studies also suggest that inducing a positive mood may produce similar effects.
Surprisingly, making drugs seem more expensive increases the nocebo effect. In one study, participants reported more side effects from a skin cream in an expensive package than from an identical cream in a regular jar. Inexpensive packaging could therefore be effective in preventing the nocebo effect.
Trust in those advocating for treatment is also essential. If someone you trust, like your own doctor, tells you that a vaccine is safe and effective, you are more likely to believe them than if a politician tells you to get vaccinated.
Similarly, if a clinician you trust advises you on the effects of a treatment, it may reduce the nocebo effect. The more you trust a person, the more you will trust what they say.
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