Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses

Abstract

The placebo and nocebo effect is believed to be mediated by both cognitive and conditioning mechanisms, although little is known about their role in different circumstances. In this study, we first analyzed the effects of opposing verbal suggestions on experimental ischemic arm pain in healthy volunteers and on motor performance in Parkinsonian patients and found that verbally induced expectations of analgesia/hyperalgesia and motor improvement/worsening antagonized completely the effects of a conditioning procedure. We 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-HT(1B/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 responses 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.

Figure 1.

Experimental and control groups for each experimental paradigm (pain, Parkinson's disease, hormone secretion) used in the present study.

Figure 2.

The effects of verbally induced expectations and pharmacological conditioning on pain tolerance. A, Natural history of tolerance to ischemic arm pain over 4 consecutive days. B, Verbal suggestion of analgesia (placebo) on day 2 induces an increase in tolerance. C, Suggestion of hyperalgesia (nocebo) on day 2 induces a decrease in tolerance. D, Suggestion of analgesia on day 4 after a 2 d preconditioning with ketorolac (ket) induces a larger increase in tolerance than verbal suggestion alone in B. E, The same ketorolac preconditioning is totally ineffective, however, if suggestion of hyperalgesia is given on day 4. Pla, Placebo; Noc, nocebo.

Figure 3.

The effects of verbally induced expectations on motor performance in Parkinsonian patients with implanted stimulating electrodes in the subthalamic nuclei. After the stimulator (Stim) had been turned off several times, a sham turning off (nocebo) induces a velocity decrease (•). This decrease is completely blocked (○) by the opposite verbal instruction (placebo). The broken line represents the natural history.

Figure 4.

Natural history of GH (A) and cortisol (B) plasma concentrations for 3 consecutive days. Note that the mean concentrations do not change either during an observation period of 90 min or over a period of 3 d.

Figure 5.

Verbal suggestions of GH increase (A) and decrease (B) have no effect on GH plasma concentration. C, After 2 d of sumatriptan preconditioning, suggestion of GH increase (Placebo) mimics the effects of sumatriptan. D, This effect is not caused by the suggestion itself, however, because the same sumatriptan-like effect is present after the opposite verbal instruction. *p < 0.05; **p < 0.03; ***p < 0.01.

Figure 6.

Verbal suggestions of cortisol decrease (A) and increase (B) have no effect on cortisol plasma concentration. C, After 2 d of sumatriptan preconditioning, suggestion of cortisol decrease (Placebo) mimics the effects of sumatriptan. D, This effect is not caused by the suggestion itself, however, because the same sumatriptan-like effect is present after the opposite verbal instruction. *p < 0.04; **p < 0.02; ***p < 0.01.

Figure 7.

Model to explain the findings of the present study. During a placebo procedure, conscious physiological processes, such as pain and motor performance, are affected by verbally induced expectations, even though a conditioning procedure is performed. By contrast, unconscious physiological processes, such as hormone secretion, are totally unaffected by expectations, whereas they are influenced by placebos through unconscious conditioning mechanisms.