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  • Updated 06.11.2024
  • Released 10.09.2023
  • Expires For CME 06.11.2027

Placebo and nocebo effects in neurologic disorders



Most of our knowledge on the placebo effect comes from pain studies, although these effects have been described in other clinical conditions, such as Parkinson disease and depression; from different systems, like the endocrine and immune systems; and even outside the medical domain, as in sports performance (14; 02; 46; 04) and oxygen-dependent functions (06; 45). In fact, the placebo effect pervades our everyday life, at the conscious and unconscious level, influencing our evaluations and decisions. Interested readers are referred to several reviews and books that address these topics in greater detail (27; 03; 04; 07; 17; 47; 18).

Key points

• Placebo effects are the positive outcomes that might follow placebo administration and are due to the psychosocial context surrounding the therapeutic act.

• Nocebo effects are represented by negative outcomes that follow the administration of an inert treatment.

• When an active treatment is given, the overall response results from both the treatment itself and the psychosocial context in which it is delivered, namely the placebo or nocebo component of the therapy.

• According to Pavlovian conditioning, aspects of the clinical setting (eg, physical characteristics of a pill or white coats) can act as conditioned stimuli, eliciting a therapeutic response in the absence of an active principle, just because they have been paired with it in the past.

• Patients’ expectations have a crucial role in the placebo and nocebo effects, whereby patients consciously foresee a positive or negative outcome. This anticipation of the future outcome, in turn, triggers internal changes and results in specific experiences.

• There is not a single placebo or nocebo effect but many. The most studied and best-understood models of placebo and nocebo effects include pain, Parkinson disease, depression, and social anxiety, as well as both immune and endocrine systems.

• The psychosocial stimuli surrounding the patient and the therapy may trigger active processes in the patient’s brain, such as activating receptor pathways that are the same as those modulated by drugs.

• Some genotypes related to high or poor responsiveness to placebos have been identified in medical conditions such as major depression, social anxiety, and irritable bowel syndrome.

• The effectiveness of the active treatment can be assessed either by eliminating its specific effect (placebo study) or by eliminating the patient’s expectations of benefit (hidden treatment administration).

• Every effort should be made to enhance the placebo component to maximize the benefit of the therapeutic act. This behavior, which relies mainly on an empathic, skilled, reassuring, and encouraging patient-provider relationship, is perfectly acceptable and does not challenge ethical imperatives.

Historical note and terminology

• Our knowledge of the placebo effect mostly comes from pain studies and Parkinson disease observations.

• Placebo response is produced by the placebo psychobiological phenomenon in addition to other potential factors, whereas placebo effect is produced by the psychobiological phenomenon only.

• The response to active treatment comes from the treatment itself and the psychosocial context, whereas in placebo administration, the response comes from the psychosocial context only.

A placebo is often defined as an inert treatment. The adjective “inert” correctly suggests that the substance or treatment is devoid of specific effects for the condition being treated. However, it cannot, by definition, be inert if it produces an effect. The solution to the conundrum can be found by shifting the attention from the treatment to the patient who receives it: it is, in fact, the symbolic meaning of the treatment, rather than the treatment itself, which by different mechanisms triggers active processes in the patient’s brain, ultimately producing the placebo effect. The placebo need not be a “treatment” either. Its archetype is, of course, the sugar pill, but more subtle or more general factors work equally well. For example, the symbolic meaning can be ascribed to one or all aspects of the context surrounding the therapeutic act, and the simulation of a therapeutic ritual can, thus, adequately replace the sugar pill. Indeed, when a medical treatment is administered, be it active or sham, it is not administered in a vacuum but in a complex set of psychosocial states and stimuli, whereby physicians and health providers certainly represent a very important component of the context, as they can transmit a lot of information to the patient through their words, attitudes, and behaviors. In the case of active treatment administration, the overall response results from both the treatment itself and the psychosocial context, whereas in the case of placebo administration, the response results from the psychosocial context only. In fact, placebo administration serves to mimic the psychosocial context: the placebo is inert, but the psychosocial context is not (Table 1).

Table 1. Psychosocial Context Considerations in Placebo Administration

Therapist-patient interaction and healthcare setting

• Empathy
• Compassion
• Skills
• Communication
• Rituals
• Hospital and room layout

Psychological and social factors

• Treatment and illness beliefs
• Environmental cues
• Past experiences
• Expectations
• Status
• Sex

The psychosocial context surrounding the therapeutic act contributes to the overall response. This includes the healthcare setting (eg, hospital and room layout, white coats, health providers, and other patients), the physical characteristics of the treatment (eg, color and shape of a pill or smell of a syrup), the patient’s and provider’s individual characteristics (eg, treatment and illness beliefs, past experiences, expectations, status, sex), and especially the therapist-patient, or patient-provider, relationship (eg, empathy, compassion, skills, communication, rituals, reassurance). This context represents the placebo component of any treatment.

The nocebo has been defined as negative placebo and, similar to the placebo, the nocebo response includes all health changes that result after administration of an inactive treatment, whereas the nocebo effect refers to the changes specifically attributable to nocebo mechanisms (24). As expectations of amelioration can lead to clinical improvement, expectations of worsening can result in negative outcomes. The term nocebo (Latin “I shall harm”) was originally introduced to designate noxious effects produced by a placebo (eg, side effects of the drug the placebo is substituting for); in that case, however, the negative outcome is produced despite an expectation of benefit. True nocebo effects, on the other hand, are always the result of negative expectations, specific or generic (like a pessimistic attitude).

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