The nocebo effect of drugs

Abstract

While the placebo effect has been studied for a long time, much less is known about its negative counterpart, named the nocebo effect. However, it may be of particular importance because of its impact on the treatment outcomes and public health. We conducted a review on the nocebo effect using PubMed and other databases up to July 2014. The nocebo effect refers by definition to the induction or the worsening of symptoms induced by sham or active therapies. Examples are numerous and concerns both clinical trials and daily practice. The underlying mechanisms are, on one hand, psychological (conditioning and negative expectations) and, on the other hand, neurobiological (role of cholecystokinin, endogenous opioids and dopamine). Nocebo effects can modulate the outcome of a given therapy in a negative way, as do placebo effects in a positive way. The verbal and nonverbal communications of physicians contain numerous unintentional negative suggestions that may trigger a nocebo response. This raises the important issue of how physicians can at the same time obtain informed consent and minimize nocebo-related risks. Every physician has to deal with this apparent contradiction between primum non nocere and to deliver truthful information about risks. Meticulous identification of patients at risk, information techniques such as positive framing, contextualized informed consent, and even noninformation, is valuable.

Keywords: Anxiety; cholecystokinin; hyperalgesia; nocebo effect; placebo effect.

Figure 1

Neurobiological mechanisms of nocebo effect. Nocebo suggestions induce anticipatory anxiety, which activates two independent pathways, a CCKergic pronociceptive system on one hand and the hypothalamus–pituitary–adrenal (HPA) axis on the other hand. Benzodiazepines act on anxiety, thus blocking both the HPA hyperactivity and the CCK pronociceptive system. CCK antagonists act on the pronociceptive system only, thus preventing nocebo hyperalgesia but not HPA hyperactivity. *Bilateral dorsal anterior cingulate cortex, insula, superior temporal gyrus, left frontal and parietal operculum, medial frontal gyrus, orbital prefrontal cortex, superior parietal lobule, and hippocampus, right claustrum/putamen, lateral prefrontal gyrus, and middle temporal gyrus. +: activation or stimulation; −: inhibition or deactivation.