The Nocebo Effect: How Negative Expectations Can Worsen Health

Edita Naruševičiūtė-Skripkienė

Introduction

The outcome of treatment prescribed to a patient can be either specific—resulting from the mechanism of a particular drug or intervention—or nonspecific. The latter includes the well-known positive placebo and negative nocebo effects, which in clinical practice often receive less attention. Placebo and nocebo effects are psychobiological phenomena that depend on the treatment context, patient expectations, previous treatment experiences, the person administering the treatment, and both verbal and non-verbal communication.

The aim of this article is to provide a more detailed overview of the nocebo phenomenon, its role in everyday medical practice and research, and how final treatment outcomes and scientific results may be influenced by it, rather than being explained solely by treatment mechanisms.

What is a nocebo?

A positive treatment outcome that occurs because the patient expects a beneficial therapeutic effect is known as a placebo (1). A nocebo is described as a worsening of symptoms, a reduction in positive effects, or the appearance of new symptoms when an inert substance (e.g., a sugar pill), an active drug, or a medical procedure is administered, and when the patient expects or has been indirectly led to believe that the treatment will be ineffective (1–3).

The term nocebo was first introduced by Walter Kennedy in 1961 (2). Research on nocebo effects has expanded only relatively recently, and therefore there are significantly fewer publications on this topic compared to placebo (1). As of August 29, 2018, a search for the keyword nocebo in the PubMed database of the U.S. National Library of Medicine yielded only 571 publications, including 97 nocebo-controlled trials. By comparison, there were 211,336 publications on placebo and 124,580 placebo-controlled trials (4).

It is important to distinguish between the nocebo effect and the nocebo response. The nocebo effect arises from a patient’s negative psychosocial environment and is typically observed in clinical practice (5). The nocebo response refers to changes caused by the patient’s negative expectations and is more commonly observed in clinical trials (6). In true double-blind drug trials, adverse events occurring in the placebo group are often attributed to the nocebo phenomenon, after excluding symptoms related to the disease itself, comorbid conditions, or the effects of other medications (1).

Individual factors influencing the risk of nocebo

There is limited data on the genetic influence on the nocebo phenomenon, although some studies suggest that patients with certain genetic variants may be more susceptible (7). For example, in a placebo-controlled trial of calcineurin inhibitors in healthy individuals, it was found that homozygous individuals with the Val158/Val158 genetic variant reported numerous psychological and physical complaints, including adverse effects typical of calcineurin inhibitors, even though they were only receiving a placebo (8).

Among individual factors, patient gender appears to play a role—nocebo responses are reported more frequently in older women than in men (1). Emotional state is also important, as nocebo responses are more common in individuals with hypochondriacal tendencies (7), who often experience heightened anxiety and increased sensitivity (1, 2).

Two neurobiological systems are particularly relevant in the nocebo mechanism: dopamine and endogenous opioids (1). Positron emission tomography studies have shown reduced activity in dopaminergic and opioid systems in patients experiencing nocebo effects. Lower dopaminergic activity has been observed in the ventral basal ganglia, subthalamic nucleus, anterior cingulate cortex, orbitofrontal cortex, anterior and posterior insula, medial thalamus, amygdala, and periaqueductal gray matter, along with reduced levels of endogenous opioids (7).

Some studies have shown that the nocebo effect may be reduced or interrupted by administering diazepam (9).

Psychological mechanisms influencing the nocebo effect

Patient expectations regarding future treatment and communication between medical staff and the patient—especially direct and indirect verbal influence (conditioning)—play a crucial role in the nocebo effect. Verbal instructions can paradoxically alter the effects of medications (2). Simply informing patients about potential adverse effects, even when they are receiving an inert substance in placebo-controlled trials, can lead to the development of nonspecific side effects characteristic of the drug being studied (1).

For example, in a study in which healthy volunteers were given nitrous oxide for pain relief and were provided with misleading information suggesting that it could increase pain, the expected analgesic effect was reversed and turned into hyperalgesia (7). In another 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 their back pain, while others were told that it would. Patients who received negative information reported stronger pain.

Nocebo phenomenon in everyday practice

In everyday clinical practice, doctors and nursing staff may unintentionally provide negative suggestions and cues when communicating with patients (1). Patients undergoing radiological examinations with contrast agents tend to experience more pain and anxiety when terms such as “burning,” “freezing,” or “hurting” are used to describe the procedure (11).

Patients are highly sensitive to negative information, especially when it relates to surgical procedures, severe illness, or accidents. In stressful or extreme situations, this sensitivity increases further, and patients may misinterpret information or become convinced of inaccurate assumptions (1).

Phrases used by medical staff that may trigger the nocebo effect are presented in Table 1.

The main areas of daily clinical practice where the nocebo phenomenon is observed are as follows:

• Informed consent. Before prescribing treatment, the physician must thoroughly inform the patient about possible adverse effects. However, negative information can contribute to the nocebo effect. Studies have shown that patients who are informed in detail about adverse reactions are more likely to experience them than those who are not. It is recommended to frame information more positively, for example, stating that most patients do not experience a particular adverse reaction rather than emphasizing how many do. Another, less commonly used approach is to educate patients about the nocebo effect itself or to obtain consent to limit detailed information, mentioning only the most important, potentially serious or irreversible adverse effects without emphasizing mild and transient reactions (1, 6).

• Treatment of neurological diseases. When managing pain, negative patient expectations—especially when reinforced by the physician’s verbal communication—can lead to psychological changes that influence not only pain perception but also the pharmacological effectiveness of treatment and clinical outcomes (3, 12). The frequency of the nocebo effect in clinical trials has been reported as follows: symptomatic migraine treatment – 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%, persistent depression – 57% (13).

• Switching from brand-name drugs to generics. Patients may report reduced effectiveness (e.g., weaker pain relief) and more frequent adverse effects, such as nausea, after switching from brand-name medications to generics (1). It has also been noted that drug packaging and labeling can contribute to the nocebo effect (14). For example, patients report more adverse effects when receiving a placebo in packaging that appears more expensive compared to one that looks cheaper (15). Although studies confirm that biosimilar drugs are effective and safe, knowledge gaps remain among both physicians and patients, which can lead to uncertainty, nocebo responses, and poorer treatment outcomes. Therefore, when switching to generic medications, physicians should clearly explain what generics are, provide scientific information if needed, and address patient concerns (16).

• Drug provocation tests for suspected allergies. During these tests, patients receiving an inert substance may still experience adverse effects associated with the tested drug. For this reason, placebo controls are recommended when performing provocation tests (1).

• Treatment of benign prostatic hyperplasia with finasteride. Patients informed that finasteride may cause erectile dysfunction report this side effect approximately three times more often than those who are not informed (17).

• Use of beta-blockers for cardiovascular diseases. In patients prescribed atenolol, erectile dysfunction occurred in 3.1% of cases when patients were unaware of the drug name. However, when patients knew the name and were informed about this potential side effect, the incidence increased to 31.2% (18).

• Lactose intolerance testing. Many individuals with lactose intolerance can tolerate small amounts of lactose (up to 10 g). In one study, patients received tablets containing only 0.03–0.5 g of lactose but still reported gastrointestinal symptoms, which were attributed to the nocebo effect (19).

Summary

Both positive and negative treatment outcomes are influenced not only by the chosen medical intervention but also by physician–patient communication and the patient’s expectations. The ability to communicate effectively and positively, alongside applying evidence-based treatment, is an essential clinical skill. Introducing communication training—such as working with simulated patients—during medical education could be highly beneficial. Continuous development of communication skills should remain a priority area for improving clinical practice.

Publication "Internistas" No. 7 2018

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