Consciousness, Placebo, and Nocebo Effects on Pain

FIGURE 9-1 The solid blue and red lines represent the analgesic responses within the long and short conditioning groups, respectively. The dashed line shows the onset and offset of the painful stimulus, as well as the duration of peak temperature. A: Prereveal placebo analgesia during thermal painful stimulation. B: Average of prereveal placebo analgesia. Long conditioning group had significant placebo analgesia, but short conditioning did not. C: Postreveal placebo analgesia. Subjects in the long conditioning group continued to demonstrate placebo analgesia postreveal, and had significantly greater placebo analgesia than the short conditioning group. D: There was no significant postreveal placebo effect in the short group. Data are presented as mean ± sem. (Data from Schafer et al. [50].)

More recently, Jensen and colleagues extended these findings by investigating the neural counterparts of nonconscious placebo and nocebo pain responses, using fMRI in healthy participants [36]. Nonconscious placebo analgesia showed increased activation of the orbitofrontal cortex as compared with conscious placebo analgesic effects. During the presentation of the masked cues, nocebo effects induced an increased activation of the thalamus, amygdala, and hippocampus as compared to the unmasked cues. Nocebo responses on pain induced an activation of the hippocampus along with the activation of the amygdala as previously reported [9, 41]. The activation of the amygdala during nonconscious nocebo responses was more highly correlated with the pain ratings indicating an unconscious motivation that may affect participants’ rating. Thus, placebo and nocebo responses can occur independently of conscious awareness [36]. These results are in line with previous studies demonstrating that fear responses also occur without conscious perception of the fear cues [47], and that the amygdala and adjacent subcortical structures facilitate an immediate, likely unconscious, recognition of threat [13].

In humans, learning is cognitively mediated and can elicit analgesia when relationships between events are acquired [48, 49]. Instructions can amplify the effect of automatic processes. A recent study included two groups of healthy subjects each receiving a conditioning procedure with or without explicit information about the cues, which consisted in distinct-colored lights anticipating either analgesia or a control level of pain, as previously used [12]. An N2–P2 component of laser-evoked potentials (LEP) was used as an index of brain responses to nociceptive stimuli and pain modulation. The group who received verbal information along with the conditioning manipulation experienced a decrease in pain rating and LEP amplitude, indicating that conscious components can reinforce automatic visual-analgesic associations [12].

Furthermore, Au Yeung and colleagues [4] investigated how partial and full reinforcement learning paradigms influence placebo analgesia. Healthy volunteers were randomly assigned continuous reinforcement, partial reinforcement, or a control (no conditioning) group. For the continued reinforcement group, the placebo was always followed by a reduction in pain during the acquisition phase. For the partial reinforcement group, the placebo treatment was followed by a reduction in pain stimulation in 62% of trials only. In the testing phase, both full and partial conditioning induced placebo analgesia, with the magnitude of analgesia being larger after the continuous conditioning. However, responses elicited by partial conditioning were less sensitive to extinction. This result indicates that partial reinforcement schedules can potentially be exploited to prevent extinction of placebo effects [4].

Also to compare continuous and partial reinforcement procedures, we tested how partial reinforcement modulates nocebo hyperalgesia and whether the effects established under partial reinforcement were more resistant to extinction as compared to those induced by full conditioning. Three key findings emerged. First, nocebo hyperalgesia can be established under partial reinforcement, although it is weaker than that established under continuous reinforcement. Second, nocebo hyperalgesia is resistant to extinction independently of whether it is established via continuous or partial reinforcement. Third, there is strong concordance between the level of hyperalgesia expected and the level experienced. These findings have a number of important theoretical and practical implications [16]. Partial reinforcement affected nocebo hyperalgesia differently than its effects on placebo analgesia. These findings were in line with previous studies showing that nocebo effects are stronger than placebo effects even when participants were merely informed about the possibility to receive high level of painful electrical shocks. Although subjects were given either tactile or low-intensity painful electrical stimuli, they reported tactile stimuli as painful and low-intensity stimuli as highly painful, indicating the possibility to create verbally induced allodynic and hyperalgesic responses. The magnitudes of the nocebo hyperalgesic effect following either verbal suggestions alone or following the conditioning procedure were not significantly different [27]. From an evolutionary viewpoint, nocebo effects may represent a form of short-term innate responses, aimed at enhancing responses to negative outcomes to initiate defensive behaviors.

AWARENESS: HOW OBSERVATION SHAPES PAIN PERCEPTION

Self-awareness is a composite of the way we see ourselves and we see others. The awareness of our identity (therefore our perceptions) results from the integration of information acquired through first-hand experiences and observation of both others’ experiences and environmental cues outside of our self. Both direct experience and observation influence the formation of placebo and nocebo effects. Healthy subjects who have witnessed a benefit in another person showed strong placebo analgesic effects comparable in magnitude to those induced through direct conditioned experiences [20]. When tested for pain following the observational phase, observers experienced as analgesic, stimuli that were actually set at a painful level. Interestingly, observation modulates behavioral nocebo effects: observing another person in pain induced hyperalgesic effects when control painful stimuli were delivered later [54]. Psychosocial cues and the entire set of interpersonal interactions also contribute to induce expectations and potentially consolidate analgesia.

Recently, a social contagion has been demonstrated, whereby informing a single subject of the possibility of headache produces a propagation of this negative information across several subjects, who will also experience headache. Interestingly, this social propagation may change the brain biochemistry of the socially infected individuals, as shown by the increase in cyclooxygenase activity and prostaglandins synthesis [8]. This phenomenon occurs in clinical encounters whereby patients interact with each other sharing experiences, feelings, and emotions. The relevance of these factors has not been investigated, but it is evident that placebo and nocebo effects have clinical implications [6, 23, 45].

MEMORY OF EFFICACIOUS OUTCOMES

Learning from prior positive experience can create strong memory analgesic responses, and likewise negative previous experiences can elicit nocebo effects. We designed a study in which one group received a treatment perceived as efficacious (actually, the intensity of painful stimulations was surreptitiously decreased) and a second group received a treatment perceived as ineffective (verbal suggestions with no manipulation of the intensity of painful stimulation). When tested for placebo analgesia the first group reported significant reduction of pain (49.3%), while the second group reported a smaller pain reduction (9.7%) [19]. After 4–7 days, both groups were retested for placebo analgesia, and we found that the placebo responses following the effective procedure were significantly higher than that observed after the ineffective treatment (29% vs. 18% pain reduction). Therefore, placebo and nocebo effects are shaped by learning (either positive or negative prior experience), and the effect of initial treatment exposure influences the response to subsequent placebo responses with obvious clinical implications [19].

Distinct neural correlates underpin the role of treatment history in placebo and nocebo effects. After randomizing healthy volunteers to two groups, either a positive or negative treatment experience, Kessner et al. [40] introduced a new analgesic to test for the effect of treatment history in an elegant fMRI study. The therapeutic effect of the tested treatment was lower in the negative compared to the positive treatment history group. The adverse effect of the negative treatment history was sustained in the brain by a higher activation of posterior insula bilaterally, a region implicated in the afferent nociceptive processing, and a lower activation of the right dorsolateral prefrontal cortex (dl-PFC), involved in pain modulatory system [40]. These findings showed how therapeutic experiences affect modulatory systems and responses to subsequent treatments and placebos.

Notably, similar effects have been documented in patients with chronic neuropathic pain [3]. André-Obadia and colleagues studied the effects of true and sham repetitive transcranial magnetic stimulation (rTMS) in a crossover design in neuropathic pain patients resistant to pharmacological treatment. Patients were assigned to one of two conditions: (1) sham rTMS delivered before the conventional stimulation of the motor cortex, and (2) sham rTMS delivered after the conventional stimulation of the motor cortex. Those patients who received the sham rTMS after a session of real rTMS perceived an analgesic effect (11% pain reduction), suggesting that the exposure to effective treatments induces the formation of significant hypoalgesic responses [3].

PLACEBO EFFECTS UNDER ALTERED STATES OF CONSCIOUSNESS: SLEEP AND HYPNOSIS

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