The nocebo effect: should we be worried?

Abstract

Lack of adherence to therapeutic regimes and side effects observed in placebo arms are common problems in randomized clinical trials and practice [1]. These effects can be partially due to the occurrence of negative placebo effects, the so-called ‘nocebo effects’. Nocebo effects rely on a phenomenon that is opposite to placebo, in which expectations of worsening play a crucial role. Recent neuroanatomical and neurochemical advances support the notion that specific modulators and brain areas are involved in the formation of nocebo effects. Negative expectations can produce increases in pain experienced and can interfere with the therapeutic action of active drugs. It has been reported that the negative and positive disclosures interfere with the analgesic efficacy of the μ-opioid agonist, remifentanil [2]. A positive communication such as, “you are going to receive a potent analgesic medication,” substantially enhanced (doubled) the analgesic effect of remifentanil. Conversely, a negative disclosure such as informing a health volunteer that the painkiller is going to be stopped when in actuality, was continuously administrated, abolished the remifentanil-induced pain relief. The subjective pain reports correlated significantly with modifications in specific brain regions that are known to be involved in pain processing [2]. Studies in human models have also indicated that the CCK system is linked to nocebo effects, at least in the field of pain. Verbal cues of increased pain produce the anticipated effects and these effects can be reversed by administering the nonspecific CCK-antagonist proglumide, suggesting that blocking CCK-A and -B receptors antagonizes verbally induced increases in pain. Furthermore, sensorial stimulations that would never normally produce pain began to do so under verbal suggestions of hyperalgesia [3]. Nocebos can produce deleterious effects as nonpainful tactile stimuli can become painful and hyperalgesic responses in which low-intensity painful stimuli are perceived as highintensity stimuli [4]. Apparently, direct experience matters in nocebo responses, but less than the placebo counterpart in which learning from previous positive experience is fundamental for consolidating positive outcomes. We can speculate that nocebos induce short-term innate responses that are aimed at enhancing the perceptual processing and at anticipating negative outcomes, which in turn help initiate potentially defensive behavioral reactions. On the other hand, perpetuation of unsuccessful experiences may promote the consolidation of negative outcomes and the severity of symptoms. From a clinical point of view, it is plausible to think that if nocebos and negative verbal cues are powerful in eliciting negative outcomes in laboratory settings, it is licit to postulate that the doctor’s words and attitudes can induce immediate worsening of symptoms [5]. For example, communication about the interruption of a therapy (pharmacological or non-pharmacological) results in the occurrence “Research on nocebo effects affirms the need for rethinking the ethics of patient–clinician communication, informed consent and, perhaps more importantly, the decision-making processes.”