Conscious & Unconscious Placebo / Nocebo Effects

The placebo and nocebo effect is believed to be mediated by both cognitive ( expectations) and conditioning mechanisms. Little is known about their role in different circumstances. In a study conducted by Benedetti et al. (2003), the effects of opposing verbal suggestions on experimental ischemic arm pain in healthy volunteers and on motor performance in Parkinsonian patients was analyzed. It was found that verbally induced expectations of analgesia/hyperalgesia and motor improvement/worsening antagonized completely the effects of a conditioning procedure. The researchers also measured the effects of opposing verbal suggestions on hormonal secretion and found that verbally induced expectations of increase/decrease of growth hormone (GH) and cortisol did not have any effect on the secretion of these hormones. However, if a preconditioning was performed with sumatriptan, a 5-HT1B/1D agonist that stimulates GH and inhibits cortisol secretion, a significant increase of GH and decrease of cortisol plasma concentrations were found after placebo administration, although opposite verbal suggestions were given. These findings indicate that verbally induced expectations have no effect on hormonal secretion, whereas they affect pain and motor performance. This suggests that placebo effects are mediated by conditioning when unconscious physiological functions such as hormonal secretion are involved, whereas they are mediated by expectation when conscious physiological processes such as pain and motor performance come into play, even though a conditioning procedure is performed.

At least two main findings emerge from this study. First, analgesic and motor placebo responses appear to be mediated by verbally induced expectations. Although the subjects' expectations were not directly measured, many studies shows verbal suggestions affect expectations. Opposite verbal suggestions modulated pain in contradictory directions and most important, even after a pharmacological analgesic preconditioning, a significant hyperalgesic effect occurred when suggestion of pain increase was given This indicates that the placebo effect of was caused by expectation of analgesia and not by the pharmacological preconditioning per se. This can also be seen in Parkinsonian patients, whose motor worsening appears to depend on verbally induced expectation; in fact, the opposite verbal suggestion was enough to reverse this effect. The second important finding is that verbally induced expectations of hormonal increase and decrease had no effect on hormonal plasma concentrations. However, placebo administration after sumatriptan preconditioning mimicked the effects of the sumatriptan itself. It is important to point out that these sumatriptan-like effects occurred regardless of whether verbal suggestions were given for GH increase or decrease. Thus verbal manipulations that are likely to affect expectations did not influence hormonal secretion.

“[I]n the present study, conditioning appears to play a crucial role in the placebo responses of human unconscious physiological functions, whereas expectations replace conditioning when conscious perception is involved (e.g., pain and motor performance).” Benedetti et al., 2003

The two key mechanisms underpinning placebo effects and nocebo effects are expectations, and conditioning (Pavlovian, Classical Conditioning). The mechanism explaining the placebo or nocebo effect depends on the context. In some cases conditioning and expectations may contribute to the effect, while in others one or the other may be involved. However, some have pointed out the conditioning is a form of expectation. Thus, if this is the case conditioning always involves expectation, whereas the reverse may not be true.