Nocebo: Placebo’s Dark Side

Tina Ryman, MSSenior Medical Writer

Most people are familiar with the placebo effect—the therapeutic benefit derived from a patient’s belief in the efficacy of a medically inert substance or sham procedure. This same power of suggestion can work in a negative way, whereby patients experience side effects. This is the known as the “nocebo effect.”

Physicians are legally and ethically bound to explain a recommended medicine’s benefits and risks as well as disclose the possible side effects that might occur. However, in the very process of describing side effects, physicians are potentially building negative expectations in their patients, which, in turn, can induce a nocebo response.

In Latin, “placebo” means “I will please,” whereas “nocebo” means “I will harm.”

Why should we as health educators be concerned about the nocebo effect? Because the damage it can cause is very real, including the following:

  • Nonadherence to or discontinuation of treatment
  •  Frequent changes in medications resulting in suboptimal care
  •  More frequent physician and emergency room visits
  •  Increased cost of medical care
  •  Psychological distress
  •  Increased dropout rate of clinical trials

Nocebo responses can be nonspecific or specific

Common nonspecific symptoms include trouble concentrating, headache, drowsiness, nausea, dizziness, insomnia, and vague malaise. These cannot be necessarily attributed to the pharmacologic action of the drug involved or the dosage. Moreover, these symptoms may be present before the patient starts taking the drug. In contrast, specific symptoms are directly related to the pharmacologic action of a drug and/or its disclosed adverse effects.

Examples of specific symptoms

Although nonspecific symptoms are the most common manifestations of a nocebo response, specific symptoms have been well documented in clinical studies.

One dramatic example is found in a study of the incidence of erectile dysfunction (ED) among men treated with beta blockers (no placebo was used). Among the patient subgroups, the researchers found

  • The group who were not told the name of the medicine nor informed of the ED side effect had the lowest incidence of ED (3.1%)
  •  The group who were told the name of the medicine but not informed about the ED side effect had a 15.6% incidence of ED
  •  The group who were told the name of the medicine and informed of the ED side effect had the highest incidence of ED (31.2%)

Another dramatic example is provided by a study of 2 placebo groups who received no medication at all. One group received placebo acupuncture therapy and the other group received a placebo pill for the antidepressant amitriptyline. Each group reported the specific side effects associated with their respective placebo treatment. Although the acupuncture group reported pain during treatment, increased pain after the so-called "needles" were removed, and local redness or swelling, the pill group reported drowsiness, dry mouth, restlessness, dizziness, and headache.

In a study of aspirin and another blood thinner in patients with heart disease conducted at 3 different medical centers, patients at 2 sites were warned about possible gastrointestinal problems and patients at the third site were not warned. The researchers found that the patients who were warned about gastrointestinal problems were nearly 3 times as likely to report those side effects as the patients who were not warned. In addition, although the researchers found a similar amount of actual stomach damage in the 3 patient groups, they noted that the patients who were informed of the side effect were the most likely to report pain.

What factors can promote a nocebo response?

Contributing factors for a nocebo response include

  • Psychological state of the patient: Anxiety, depression, and hypochondria can increase susceptibility to a nocebo response. Somatization refers to psychological distress that is converted into physical symptoms
  •  Past negative experiences: Patients who experienced side effects in the past are more likely to experience side effects again, triggered by sights, sounds, or other cues associated with the negative past experience. Some patients who have undergone chemotherapy reportedly became nauseated or vomited upon entering the room where they had previously received chemotherapy
  •  Pill color: Symbolically, blue and green colors suggest sedation, and yellow, orange, and red colors suggest stimulation. In studies, patients taking blue placebo pills were more likely to report feeling drowsy than patients taking pink pills
  •  Verbal suggestion: The words physicians use to explain possible side effects can be enough to create expectations about outcomes. Informed consent forms can also influence expectations

Strategies for minimizing nocebo responses

The nocebo effect presents an ethical dilemma for physicians: on one hand, full disclosure of possible side effects is required by established ethics of informed consent—yet, on the other hand, detailed disclosure may produce harm. Despite this ongoing dilemma, there are some strategies that physicians can use to help avoid or at least minimize a nocebo response.

  • Reframing an adverse event in a more positive, reassuring way: This approach gained validation from a study of women in labor receiving epidural injections for pain. One group was told, “You are going to feel a bee sting; this is the worst part of the procedure.” The other group was told, “We are going to give you a local anesthetic that will numb the area and you will feel comfortable during the procedure.” The group hearing the latter statement reported significantly less pain than the women hearing the former statement. Another study found less reported pain when thephysicians replaced the word “pain” with the phrase “cool sensation.”
  • Evaluating and monitoring the patient’s psychological state: anxiety, depression, and hypochondria increase patients' risk for a nocebo response. These emotional states should put physicians on high alert for tailoring their message carefully
  • Educate the patient about the relationship between emotions, physical sensations, and stress hormones: This step empowers the patient to make a conscious effort to keep negative emotions in check before they manifest physically
  • Ask the patient to share his or her earlier disappointing experiences with a treatment or procedure: If the patient indeed has had a bad experience, the physician can suggest the patient resist expecting a similar experience, as such anticipation can be a self-fulfilling prophecy
  • Demonstrate behaviors that establish trust and promote the patient’s participation and cooperation: Patients who trust their physicians and are actively engaged in the decision-making process are in a position of strength and, as such, more resistant to a nocebo response

An opportunity for education

Although the nocebo effect poses a dilemma for physicians, it creates an opportunity for health educators. In all likelihood, this issue is not exactly top of mind among busy, overworked physicians. So it becomes our task to help raise awareness amongphysicians of the strong impact their choice of words can have on patients. We need to create solutions that facilitate the implementation of the strategies discussed above and that may, in turn, help enhance quality of care and patient outcomes.

Artcraft Health has many years of experience in creating educational solutions targeted to healthcare professionals as well as patients. One of our specialties is creating counseling materials that support a more open and collaborative dialogue between the physician and patient. These solutions incorporate insights, strategies, and prompts that assist the healthcare professional in discussing important issues, addressing individual patient needs, and minimizing expectation gaps in treatment. Such education empowers patients and physicians to focus on the treatment objective and establish an open dialogue. At Artcraft Health, we believe improving patient-physician communication starts with the appropriate educational solution at the point of care, with the right message at the right time.

Further reading:

Collaca L, Finniss D. Nocebo effects, patient-clinician communication, and therapeutic outcomes. JAMA. 2012; 307(6):567-568.

Wells R, Kaptchuk TJ. To tell the truth, the whole truth, may do patients harm: the problem of the nocebo effect on informed consent. Am J Bioeth. 2012; 12(3)22-29.