Importance and Role of Placebo Effects in Clinical Trials and Treatment: A Narrative Review

Any treatment method, material, symbol, ritual, or word that has an indirect or non-specific effect is called a placebo or sham. A placebo is described as an ineffective substance, such as injecting saline or a sweet pill, or simulating a treatment that may not have a direct effect on a particular variable but can improve the symptoms of a disease. The term "placebo effect" refers to any therapeutic effect due to the use of a placebo agent, although that agent has no specific biological effect (1). Placebo effects and favorable outcomes resulting from the patient's expectation of treatment should be considered a powerful tool for treatment. In addition, the collaboration between therapist and patient creates the basis for placebo effects (4). However, patient expectations and the patient-therapist relationship, as well as the history of previous treatments, can also have adverse effects and impair treatment. Adverse effects, as opposed to placebo effects, are called nocebo effects (6).Placebo needs different mediators to work. The central nervous system (CNS) is the main station and physiological mediator of placebo effects through memory and learning. Commands related to the sensory, motor, automatic, and immune systems are issued from this station. People have certain individual traits that enable them to respond more or less to a specific stimulus (14). Different mechanisms are described for both placebo and nocebo effects. The characteristics of the treatment environment can act as a conditioned stimulus and evoke a therapeutic effect in the absence of the active therapeutic agent. The conditioned response can also be generated as a nocebo effect. For example, nausea can recur when a patient observes an environment where he or she has undergone chemotherapy in the past. Associate learning, which creates a placebo effect, can be achieved through conditioning. While the relative role of conditioning is not clear, conditioning is an important unconscious mechanism, especially for placebo effects on the immune or endocrine system (21). In addition to conditioning, expectation is also influential as a cognitive issue. The patient consciously predicts the outcome of treatment, positively or negatively (15). Expectation is affected by a person's emotional evaluation of the situation, such as fear, anxiety, or expectation of reward. However, the patient's previous experiences or emotional factors can have a positive or negative placebo effect (24). The computational and mindset models are the other psychological mechanisms behind placebo effects. The difference in the amount and accuracy of expectations that affect the strength of placebo effects in the field of pain can be explained by the Bayesian computational model based on a predictive coding framework (27). Mindsets are frameworks that lead people to shape associations or beliefs about situations or experiences (4). Research on the effect of mindsets on stress response has shown that using the physiological capacity of stress responses to improve performance and cognitive capability, instead of negative perceptions of stress, leads to a more adaptive cortisol state. That means a less cortisol for those with a high cortisol response and a high cortisol for those with a lower cortisol response to stress (26).The results of research related to placebo show that it calms down patients, prevents the prescription of unnecessary drugs, and is used as a complementary therapy. The purpose of using a placebo is not necessarily to deceive. Placebo may thus be an effective treatment; not using it can even be unethical (1). Research in the field of placebo has been conducted for various conditions. High placebo response rates have been reported for Parkinson's disease. Numerous studies have been conducted to investigate the neurobiological basis of placebo responses in Parkinson's disease. It has been determined that the improvement in mobility in these patients is due to the release of dopamine and the activation of the entire pathway from the substantia nigra to the striatum. This can be obtained by stimulating the subthalami region and using a placebo. In addition, the extent of the placebo effect depends on the expectation of recovery, which in turn is associated with the release of dopamine (35). Researchers have also reported placebo-induced improvements in patients with multiple sclerosis (37), epilepsy (38), and depression (19).The purpose of a placebo in clinical trials is exactly the opposite of that in clinical conditions. That is, to limit and reduce the placebo effect as much as possible in order to isolate the pure effect of a particular treatment. Research into placebo mechanisms has at least two important implications for clinical trials: one is to design protocols to circumvent the need for placebo groups. The other is to re-evaluate the methodology of clinical trials. In fact, patient expectations are usually uncontrollable. However they have the potential to affect both the placebo group and the active treatment group distinctly. As a result, attempts to isolate the pharmacodynamic effects would be impossible (41). In clinical trial studies, the adverse effects observed in the active treatment group and the placebo group were often influenced by non-specific factors. The rate of adverse effects reported in placebo groups in clinical trial studies can be quantified using a systematic review. Participants in a double-blind randomized clinical trial know that they will receive either an active drug or a placebo and are aware of any adverse effects they may experience. This information is contained in the informed consent form and provided through instructions from the examiner. Informing participants about possible adverse effects they may experience significantly impacts their expectations (14). The patient's belief regarding allocation to an active treatment group or a placebo group may be more effective than the active drug itself. This is the case in surgery for Parkinsonian patients (33). However, patient expectations have not yet been assessed in a clinical trial or included in the analysis. In routine clinical treatments where a known drug is given to patients, the efficacy of the drug is due to a combination of a nonspecific placebo effect and a biologically active effect. In double-blinded placebo-controlled trials, a direct biological effect is assumed to be the difference between the active and placebo groups. However, because the direct biological and nonspecific effects of placebo may not be solely additive, it is not easy to draw conclusions from double-blind placebo-controlled trials (10). Informed consent may alter the effectiveness of a placebo compared to an active agent in a situation where medications are prescribed to patients without providing information related to the study (45). The placebo effect may be very large for non-blinded interventions. This may lead to an efficacy paradox (46). This happens, for example, when a treatment is effective compared to a drug but has little therapeutic effect compared to a placebo. However, all treatments must meet a high standard to demonstrate their advantage of treatment over the control group. This may occur in surgeries in which nonspecific beneficial effects are prominent, but sham surgery is not used as a control. The same is true for other methods in which blinding is not possible, such as in the case of acupuncture, in which nonspecific effects may be part of the treatment (47). While it is very important to have a consistent control group with expectations with an active intervention, designing an ideal control group for specific interventions, such as psychological and behavioral interventions, may be difficult or impossible. Therefore, knowing the effects of placebo and their biological infrastructure, and considering them in clinical trials, helps to better interpret clinical trials.Various methodological factors may confound placebo effect studies when analyzing and interpreting the results of clinical trials. This means that placebo effects do not include methodological factors that reflect improvement, because these factors are not related to the active change of the measured variable. These factors, including the Hawthorne effect, regression to the mean, therapist, and observer bias, can distort the results of placebo studies. Ignoring these factors leads to misinterpretation of the results of studies related to the placebo effect. In designing randomized clinical trials, therefore, having a control group without intervention and perhaps measuring expectancy are vital elements that can help isolate placebo effects from these confounding factors.In conclusion, the placebo and nocebo effects are complex phenomena that encompass the psychological, biological, neurological, and individual dimensions of human physiology and behavior. The concepts and mechanisms of placebo and nocebo effects can be described by different models and frameworks. Understanding the effects of the placebo can help physicians, therapists, and healthcare providers to improve clinical situations and environments for patients by providing positive expectations through conditioning. On the other hand, limiting the placebo effect as much as possible is recommended in designing clinical trials in order to isolate the net effect of a given treatment.