Placebo Analgesia in Dementia

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The psychosocial context surrounding the patient and the psychobiological model offer interesting perspectives from which to study the placebo analgesic response. Some authors use the term placebo response to mean any type of improvement that may take place in a placebo group of a clinical trial, even if that improvement is related to statistical artifacts such as sampling bias and regression to the mean, or to the natural history of a clinical condition. Importantly, the term placebo response should only be reserved for an active neurobiological process that occurs as a result of a dummy treatment. Indeed, brain activity changes related to the psychosocial context in the form of a procedure to elicit placebo analgesia (PA) allow us to describe, through a variety of approaches, the specific neurophysiological effect. The interesting aspect of studying PA lies in the fact that the specific effects of a drug are removed to collect the effects of a positive psychosocial context on the patient’s responses. Likewise, the open–hidden paradigm allows us to differentiate the specific effects of an active drug from those of a positive psychosocial context [5, 7, 14]. Indeed, through this, it is possible to dissociate the benefit of the psychosocial context where the treatment is overtly given from the pharmacodynamics effect of the treatment itself. Interestingly, the results obtained through these studies demonstrate that the same drug at the same dosage and with the same infusion time is more effective when it is administered overtly rather than covertly.

Contextual information leading to placebo responses arises either from conscious expectancies about a positive anticipated treatment effect or from prior learning in the form of conditioning with active treatments [1]. The context surrounding the administration of a placebo may lead individuals to expect improvement and positive outcomes. On the opposite side, negative contextual information can lead individuals to expect a worsening of symptoms, which in turn can produce a nocebo effect. One way to identify nocebo effects is the analysis of side effects in placebo groups of randomized double-blind placebo-controlled trials [4].

The importance of these studies in medical practice is represented by the possible exploitation to the patient’s advantage, so that the placebo component of a therapy can be maximized and nocebo side effects minimized. This aspect should be, for example, considered in patients with cognitive impairment related to dementia who, compared with mild cognitive impaired patients, are more vulnerable to feel adverse events of symptoms even during a placebo treatment [3]. Another crucial aspect is represented by the disruption of placebo mechanisms, which may require increased therapeutic doses of drugs to compensate for the loss of the placebo response, as described below [8, 10].

In this chapter, we try to answer specific questions regarding patients with cognitive impairment, even though we have only a limited understanding of the neurocognitive factors that influence patients’ response to placebo. We first analyze the role of the prefrontal cortex in the placebo analgesic response; then, we describe some recent studies that investigated PA when an impairment of prefrontal functioning occurs.

THE PREFRONTAL AREAS IN Placebo Analgesia

Modern brain imaging techniques have been fundamental in the understanding of PA, and many brain imaging studies have been carried out to describe the functional neuroanatomy of the placebo analgesic effect [11, 16, 17, 20, 22, 26, 28, 30, 34, 35, 40, 41, 45, 46, 48, 49, 51, 52].

The first imaging study of PA showed that a subset of brain regions is similarly affected by either a placebo or a µ-opioid agonist [34]. In particular, the administration of a placebo induced the activation of the rostral anterior cingulate cortex, the orbitofrontal cortex, and the anterior insula, and there was a significant co-variation in activity between the rostral anterior cingulate cortex and the lower pons/medulla, and a subsignificant co-variation between the rostral anterior cingulate cortex and the periaqueductal gray, suggesting that a descending pain-modulating circuit is involved in PA. Experimental evidence shows that this modulating descending circuit, as described by Fields and Basbaum [18], involves the spinal cord [17, 19, 29].

In a functional magnetic resonance imaging study of experimentally induced pain in healthy subjects, Wager et al. [48] found that PA was related to decreased neural activity in pain-processing areas of the brain. Pain-related neural activity was reduced within the thalamus, anterior insular cortex, and anterior cingulate cortex during the placebo condition as compared with the baseline condition. The magnitudes of these decreases were correlated with reductions in pain ratings. Wager et al. [48] did analyze not only the time period of pain, but also the time period of the anticipation of pain. They hypothesized increases in neural activity within brain areas involved in expectation, and indeed, they found significant positive correlations between increases in brain activity in the anticipatory period and decreases in pain and pain-related neural activity during stimulation within the placebo condition. The brain regions showing positive correlations during the anticipatory phase included the orbitofrontal cortex, dorsolateral prefrontal cortex, rostral anterior cingulate cortex, and midbrain periaqueductal gray. The dorsolateral prefrontal cortex is a region that has been associated with the representation and maintenance of information needed for cognitive control, consistent with a role in expectation [32]. On the other hand, the orbitofrontal cortex is associated with functioning in the evaluative and reward information relevant to allocation of control, consistent with a role in affective or motivational responses to anticipation of pain [15].

The anterior cingulate cortex is often reported to be involved in PA, although some discordant results have been obtained. For example, it was found to have increased activity in a study by Petrovic et al. [34] and decreased activity in a study by Wager et al. [48], which might be explained on the basis of the different experimental settings.

Most of the brain imaging studies aiming at investigating PA have been performed in experimental settings using healthy volunteers. By contrast, Price et al. [35] conducted a functional magnetic resonance imaging study in which brain activity of irritable bowel syndrome (IBS) patients was measured in response to rectal distension by a balloon barostat (a tonic pain stimulus). In particular, the patients were placed in the scanner and the experimenter applied the same agent to the balloon for each condition (saline jelly), just before the balloon was inserted. However, in the rectal placebo (RP) condition, the experimenter told the patients, “The agent that you have just received is known to powerfully reduce pain in some patients.” This suggestion is identical to that used in previous studies by the same group and is one that could be ethically applied during some active treatments. A large placebo effect was produced in the RP condition and accompanied by large reductions in neural activity in the thalamus, the primary and secondary somatosensory cortices, the insula, and the anterior cingulate cortex during the period of stimulation. It was accompanied by increases in neural activity in the rostral anterior cingulate cortex, bilateral amygdala, and periaqueductal gray [36]. This study is quite important and informative, as it shows that placebos act on the brain in a clinically relevant condition (indeed IBS is considered a clinically relevant model of PA) in the same way as they do in the experimental setting. Therefore, the involvement of key areas in PA, such as the anterior cingulate cortex, not only is limited to experimental noxious stimuli, but also extends to clinical pain. The study by Price et al. [35] is also interesting because reductions in brain activity occurred during the stimulus presentation itself, not just when subjects reported pain. In fact, it has been argued that the length of the painful stimulation may be critical for the measurement of placebo effects, as most studies used short heat or electric shock as pain stimuli and recorded activity decreases during periods extending after the stimulus offset, thus possibly including a later cognitive reappraisal of the significance of pain and/or late neural activity influenced by report bias.

To determine whether expectation of analgesia exerts its psychophysical effect through changes of the perceptual sensitivity of early cortical processes (in the primary and secondary somatosensory areas) or on later cortical elaborations, such as stimulus identification and response selection in the anterior cingulate cortex, Lorenz et al. [27] used high temporal resolution techniques (magnetoencephalography). They found that activity in the secondary somatosensory cortex was highly correlated with the extent of influence of the subjective pain rating by prestimulus expectation, while anterior cingulate cortex activity seemed to be associated only to stimulus intensity and related attentional engagement. In another study on laser-evoked potentials by Wager et al. [47], early nociceptive components were found to be affected by placebos. Therefore, later cognitive reappraisal of the significance of pain and/or late neural activity influenced by report bias cannot be responsible for this early modulation. This indicates that the very early sensory components are affected by placebo manipulation.

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