Unraveling the Mystery Behind the Nocebo Effect: Placebo’s Evil Twin

A study published in the June issue of the Journal of Clinical Psychiatry led by Seetal Dodd, Ph.D., an associate professor of psychiatry at Deakin University in Australia, and colleagues calls attention to the importance of considering nocebo effects in psychotherapeutic trials.

The nocebo (from the Latin “I will harm”) effect was first described as a “contrary effect” to the placebo response by Walter Kennedy in the early 1960s. Kennedy noted what he called an “unoriginal observation,” namely that many of his subjects in his clinical trials exhibited non-specific adverse reactions, and he believed that all physicians have “met the nocebo reaction, even if they have not labeled it as such. …” The nocebo effect has been called placebo’s “evil twin.”

There is not a standardized research definition of the “nocebo effect,” but essentially the effect involves a form of self-deception on the part of patients to attribute all the negative reactions they are experiencing to a psychotherapeutic or psychopharmacological intervention, including when they are administered an inert or harmless substance (that is, even when given a placebo itself). Dodd defined the effect: “…when a harmless substance creates harmful effects.”

Despite being often nonspecific (for example, headache, fatigue, difficulty concentrating) and not dose-related, the nocebo effect can have a considerable impact on a study by leading to considerable psychological distress in patients and noncompliance with treatment.

Even more troublesome, though, is that it can potentially lead to “epidemic waves” of adverse reactions whereby a medication is prematurely withdrawn from the market. Some researchers have even suggested that nocebo effects may be involved when patients report adverse reactions when they are switched from a brand name medication to the generic.

Further, there are ethical issues involved in nocebo responses involving the conflicting principles of respect for a patient’s autonomy and nonmalfeasance, (that is, Hippocrates’ “Do no harm”). In other words, there is a fine balance between burdening a patient with too much information about potential harm and creating an atmosphere of paternalism by withholding information. Furthermore, with the Internet and exposure to other media (for example, pharmaceutical advertisements on TV), patients now learn about side effects from many sources. As Gerben Meynen, Ph.D., a professor of forensic psychiatry at Tilberg University in the Netherlands, and colleagues, noted in the American Journal of Bioethics in 2012, a physician is no longer necessarily the “gatekeeper of medical information.”

Prevalence rates for nocebo effects vary, depending on the clinical situation and the intervention prescribed. In a review of 48 empirical studies published last month in the Journal of Advanced Nursing, Andrew Symon, Ph.D., M.A., a senior lecturer in nursing at the University of Dundee in Scotland, found the prevalence of the nocebo effect to be 3 percent to 27 percent.

In their review of clinical trials of antidepressants with over 2,400 subjects, Dodd and colleagues found that nocebo effects may be responsible for almost 64 percent of treatment-emergent adverse effects and almost 5 percent of discontinuation. They noted that nocebo effects are common in those given placebos during controlled trials in major depressive disorder.

Little is known about predictors of the nocebo response or about its mechanism of action. Negative expectation on the part of the patient can be a factor, as can previous negative experiences with medications or therapy. Psychological symptoms such as depression and anxiety (the very conditions for which psychiatrists medicate patients) can make some patients more prone to nocebo effects, as can a pessimistic disposition or a Type A personality. The reaction is more commonly seen in women.

Mechanisms may also involve conditioned learning, as when patients previously treated with chemotherapy for cancer develop side effects such as nausea just by seeing the nurse or entering the treatment room, even before being given another dose of medication. Researchers have noted that nocebo reactions may involve dopamine, the opioid system, and cholecysokinin, and they can activate brain structures just by the expectation of negative effects.

Many factors likely contribute to a patient’s reaction to medication, including the quality of the physician-patient relationship and what both physician and patient expect to happen. Other more superficial factors may also contribute, including a medication’s color, smell, shape, method of administration, or even its name.

Dodd and colleagues summarized their findings by noting that the nocebo effect is a “common, covert, and poorly understood” phenomenon that requires further investigation.

Reactions to medications often reflect patients’ general dissatisfactions with or negative transference to a physician. It behooves us as psychiatrists, in particular, to attempt to sort out where negative reactions originate and whether within the patient or within the treatment. ■