Nocebo in Medicine

Edita Naruševičiūtė-Skripkienė

Introduction

Treatment prescribed to a patient can lead to specific outcomes caused by the mechanism of a particular drug or intervention, and nonspecific outcomes, including well-known positive placebo and negative nocebo effects, which often receive less attention in practice. Placebo and nocebo effects are psychobiological phenomena influenced by the treatment context, patient expectations, previous treatment experiences, the person administering the treatment, and verbal and non-verbal communication skills.

This article aims to provide a detailed overview of the nocebo phenomenon, its role in everyday medical practice, and its impact on research outcomes. Recognizing the nocebo effect is important because it can influence final treatment outcomes and scientific research results, not just the mechanisms of the treatment itself.

What is a nocebo?

A positive treatment result, occurring because the patient expects a positive therapeutic effect, is known as a placebo (1). A nocebo involves a worsening of symptoms, a decrease in positive effects, or newly appearing symptoms when an inert substance (e.g., a sugar pill), an active drug, procedure, or intervention is administered, and the patient expects or is indirectly convinced that treatment will be unsuccessful (1-3). Walter Kennedy first used the term nocebo in 1961 (2). Research on nocebo has increased recently, but there are fewer publications on this topic compared to placebo (1). On August 29, 2018, searching for the keyword nocebo in the PubMed database of the National Library of Medicine of the United States yielded only 571 publications and 97 nocebo-controlled trials. In contrast, there were 211,336 publications on placebo and 124,580 placebo-controlled trials (4). The nocebo effect differs from the nocebo response. It results from the patient's negative psychosocial environment, observed in clinical practice (5). In contrast, the nocebo response, more common in clinical trials, involves changes caused by the patient's negative expectations (6). In true double-blind drug trials, all negative adverse events in the placebo group are referred to as the nocebo phenomenon, excluding all negative sensations or changes related to the disease itself, concomitant diseases, or possible effects of drugs for concomitant diseases (1).

Individual factors influencing the risk of nocebo

There is a lack of data on the genetic influence on the nocebo phenomenon, but some studies show that patients with specific genetic variants experienced the nocebo more frequently (7). For example, one placebo-controlled trial of calcineurin inhibitors in healthy individuals found that homozygous individuals with the Val158/Val158 genetic variant expressed many psychological and medical complaints, adverse effects typical of calcineurin inhibitors, even though they were only treated with a placebo (8).

Among individual factors, the patient's gender is important, with the nocebo more common in older women than in men (1). The patient's emotional state is significant, as the nocebo response is more common in hypochondriac personalities (7) who feel anxious and have increased sensitivity (1, 2).

Two neurobiological substances play a role in the nocebo mechanism - dopamine and endogenous opioids (1). Positron emission tomography has shown reduced dopaminergic and opioid system activity in patients experiencing the nocebo. Lower dopaminergic activity appears in the ventral basal ganglia, subthalamic nucleus, anterior cingulate cortex, orbitofrontal cortex, anterior and posterior insula, medial thalamus, subthalamic nucleus, amygdala, and peri-aqueductal gray area, along with reduced levels of endogenous opioids (7). Some studies show that administering diazepam to patients can halt the nocebo effect (9).

Psychological mechanisms influencing the nocebo effect

Patient expectations related to future treatment and the medical staff's communication with the patient, especially direct and indirect verbal influence (conditioning), play a role in the nocebo effect. Verbal instructions can paradoxically alter the effects of drugs (2). Informing patients that a drug can cause adverse effects can lead to the development of nonspecific adverse effects specific to the drug being studied, even if the patient receives an inert substance in placebo-controlled trials (1). For example, in a study where healthy volunteers received nitrous oxide gas to relieve pain and misleading information that it could increase pain, analgesia turned into hyperalgesia (7). In a study by M. Phlingsten (10), patients diagnosed with back pain underwent a leg bending test. Some patients were told that bending the leg would not worsen back pain, while others were told that back pain would worsen. The group of patients who received negative information experienced stronger pain.

Nocebo phenomenon in everyday practice

In daily practice, doctors and nursing staff inadvertently provide many negative hints and affirmations when communicating with patients (1). Patients undergoing radiological examinations using contrast agents experience more pain and anxiety if words like burning, freezing, or hurting are used to explain the future procedure (11). Phrases used by medical staff that can trigger the nocebo effect are summarized in Table 1. Patients are very sensitive to negative information, especially related to surgical manipulations, acute severe illness, or accidents. They become even more sensitive in extreme situations, may misinterpret the information received, and become convinced by false facts (1).

Main areas of daily clinical practice where the nocebo phenomenon is observed

1. Informed Consent of the Patient: Before prescribing treatment, doctors must inform patients about possible adverse effects. Negative information can stimulate the appearance of the nocebo effect. Studies show that patients informed in detail about adverse reactions are more likely to experience these reactions than those who are not informed. It is recommended to present statements positively, for example, saying that most patients do not experience this adverse reaction rather than emphasizing how many patients do. Another option is to educate the patient about the nocebo itself or obtain consent not to inform about everything, briefly mentioning only the most important possible adverse, irreversible reactions without emphasizing mild and transient ones (1, 6).

2. Treatment of Neurological Diseases: Negative patient expectations, reinforced by the doctor's verbal influence, can provoke psychological changes that alter not only pain perception but also the pharmacological effectiveness of treatment and clinical outcomes (3, 12). The frequency of the nocebo in clinical trials of symptomatic migraine treatment is 18.45%, preventive migraine treatment - 42.78%, tension-type headache - 23.99%, epilepsy - 60.8%, multiple sclerosis - 74.4%, Parkinson's disease - 64.7%, neuropathic pain - 52%, restless legs syndrome - 45.36%, and persistent depression - 57% (13).

3. Switching From Brand-Name Drugs to Generics: Patients report weaker pain-relieving effects and more frequent cases of nausea when switching from brand-name drugs to generics (1). Drug packaging labeling can also trigger the nocebo effect (14). Patients experience more adverse effects if they receive a placebo in a package that appears more expensive than a placebo in a cheaper-looking package (15). Though comparative studies of biosimilar drugs demonstrate their effectiveness and safety, information gaps cause uncertainty between doctors and patients, resulting in the nocebo effect and leading to poorer treatment outcomes. When switching patients to generic drugs, doctors should explain what generic drugs are, introduce scientific information if necessary, and answer patients' questions (16).

4. Drug Provocation Tests to Rule Out Drug Allergies: When receiving an inert substance during the study, patients may experience adverse effects of the drug being investigated. Therefore, it is always recommended to include a placebo control when performing provocation tests (1).

5. Treatment of Benign Prostatic Hyperplasia with Finasteride: Patients treated for benign prostatic hyperplasia with finasteride and informed that finasteride can cause erectile dysfunction experience it three times more often than those who are not informed about it (17).

6. Use of Beta-Adrenergic Blockers for Cardiovascular Diseases: Patients prescribed atenolol but unaware of the name experienced erectile dysfunction in 3.1% of cases. However, when patients knew the name and were informed about the possibility of erectile dysfunction, it occurred in 31.2% of cases (18).

7. Lactose Intolerance Tests: Many lactose intolerant patients can tolerate a small amount of up to 10 g of lactose. During the study, patients who were lactose intolerant received tablets containing 0.03-0.5 g of lactose but experienced gastrointestinal symptoms, which were considered a nocebo effect (19).

Summary

Positive and negative treatment outcomes depend not only on the prescribed treatment method but also on the doctor's communication with the patient and the patient's expectations related to the treatment. Learning how to not only prescribe treatment according to protocol but also positively influence patients is an art for doctors. It would be beneficial to teach future doctors communication skills with patient-actors during their studies. Regular communication courses with patients could be one of the priority areas for improving qualifications.

Publication "Internistas" No. 7 2018

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