The placebo response: neurobiological and clinical issues of neurological relevance

J. Verhaagen et al. (Eds.) Progress in Brain Research, Vol. 175 ISSN 0079-6123 Copyright r 2009 Elsevier B.V. All rights reserved

CHAPTER 19

The placebo response: neurobiological and clinical issues of neurological relevance Antonella Pollo1, and Fabrizio Benedetti2 1

Department of Neuroscience, Faculty of Pharmacy, University of Turin; National Institute of Neuroscience, Turin, Italy 2 Department of Neuroscience, University of Turin Medical School; National Institute of Neuroscience, Turin, Italy

Abstract: The recent upsurge in placebo research has demonstrated the sound neurobiological substrate of a phenomenon once believed to be only patient mystification, or at best a variable to control in clinical trials, bringing about a new awareness of its potential exploitation to the patient’s benefit and framing it as a positive context effect, with the power to influence the therapy outcome. Placebo effects have been described both in the experimental setting and in different clinical conditions, many of which are of neurological interest. Multiple mechanisms have been described, namely conditioning and cognitive factors like expectation, desire, and reward. A body of evidence from neurochemical, pharmacological, and neuroimaging studies points to the involvement of neural pathways specific to single conditions, such as the activation of the endogenous antinociceptive system during placebo analgesia or the release of dopamine in the striatum of parkinsonian patients experiencing placebo reduction of motor impairment. The possible clinical applications of placebo studies range from the design of clinical trials incorporating specific recommendations and minimizing the use of placebo arms to the optimization of the context surrounding the patient, in order to maximize the placebo component present in any treatment. Keywords: placebo; expectation; conditioning; pain; neurotherapy

eliminating the interfering nonspecific effects, grouped together in the placebo arm. In recent times, however, interest in the neurobiology of the placebo effect has shed light on the positive aspect of the placebo, bringing about a new awareness of its potential exploitation to the patient’s advantage and framing it as a positive context effect, with the power to influence the therapy outcome. Placebo effects have been described in many different clinical and experimental settings, many of which are of neurological interest, ranging from

Introduction The negative connotation carried by the word placebo is the heritage of decades of clinical trials in which the evaluation of the specific effect of a new treatment can be achieved only by

Corresponding author.

Tel.: +39 011 6708491; Fax: +39 011 6708174; E-mail: [email protected] DOI: 10.1016/S0079-6123(09)17520-9

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motor disorders, like Parkinson’s disease, and neuropsychiatric conditions, like depression and anxiety, to endocrine and immune systems changes (Benedetti, 2008a, b). Major effects have been observed in pain, and indeed placebo analgesia, that is, the lessening of pain experienced in response to a therapeutic act devoid of intrinsic analgesic activity, is widely used as a model to investigate the nature of the placebo response. This chapter provides a short overview of neurochemical, pharmacological, and neuroimaging studies in the current lines of placebo research. Emphasis will be placed on mechanisms of action, enlightening the role of expectation and conditioning in activating neural pathways leading to specific clinical outcomes during both pharmacological and procedural placebo administration. Also, stress will be put on how this knowledge can translate into better clinical practice, optimizing the psychosocial context surrounding the patient, enhancing the environmental factors eliciting expectation of improvement, and designing new types of clinical trials. In depth discussion of these topics can be found in a number of recent specific reviews (Benedetti, 2007, 2008a, b; Benedetti et al., 2005; Colloca and Benedetti, 2005; Finniss and Benedetti, 2005; Price et al., 2008; Enck et al., 2008).

Two different meanings of the term ‘‘placebo effect’’ The treatment nonspecific effects in the placebo arm of a clinical trial can be due to a number of different factors, which can be present in variable proportion and give a more or less important contribution to the total effect. The placebo biological phenomenon is one of them. Other factors are natural history (the time course of the symptom or disease, in the absence of any external intervention), regression to the mean (the tendency of a second assessment to give a value closer to the distribution mean), biases (e.g., the desire to please the clinician with the expected answers), and judgement errors. When the aim is the evaluation of a new treatment, as in clinical

trials, it is not important to measure these factors separately. It is sufficient to subtract their sum from the overall effect. The term ‘‘placebo effect’’ is then used to refer to this sum of factors. On the other hand, when the aim is to study the biological phenomenon underlying the placebo effect, care must be taken to dissect it from confounding factors, by including a natural history group as a control for the placebo condition. The term ‘‘placebo effect’’ is in this case more restrictive, and in the single individual, it is more precisely called ‘‘placebo response.’’ Confusion can arise if one attempts to compare results in placebo arms of clinical trials without a natural history group with neurobiological studies specifically targeted on placebo (Hrobjartsson and Gotzsche, 2001; Vase et al., 2002; Thorn, 2007).

Evolution of the sugar pill Traditionally, a placebo was a carbohydrate tablet given with the intent of soothing an otherwise incurable patient or detecting a mystifying one through the success of the sham therapy. By definition, however, the tablet content is absolutely irrelevant: the placebo effect is triggered not by the sugar but by the symbolic significance that the patient attaches to it (Brody, 2000). In fact, virtually anything can work as a placebo, by inducing expectations of improvement which in turn trigger internal changes resulting in specific experiences (e.g., analgesia or motor improvement) (Kirsch, 1999). Thus, all aspects of a therapy (the physician’s words, the sight and smell of the environment, the memory of past experiences in similar situations, etc.) can carry healing meaning, rendering the placebo effect a context effect (Di Blasi et al., 2001; Benedetti, 2002). At the limit, research protocols can be applied where no placebo is actually given, but the context effect is elicited only by verbal suggestions or other environmental clues inducing expectation of benefit. In this way, the simulation of a therapeutic situation is an effective substitute for the sugar pill, as shown by sham acupuncture studies where consistent placebo effects could be achieved when the complex healing environment was reproduced

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in all details except needle insertion (Bausell et al., 2005). To say that anything can work as a placebo does not mean that all placebos are equal. In fact, differences in the magnitude of the response have been reported comparing routes of administration (De Craen et al., 2000) or inert pills versus sham devices (Kaptchuk et al., 2006). In all probability, these differences are attributable to the variable potency in raising expectations. Depriving the patient of the contextual clues about a therapy can also represent a means of evaluating the placebo effect. In this case, a comparison is made between open and hidden administration of a drug, in full view of the patient or by a computer-controlled infusion pump, respectively. When the patient does not expect a treatment, the placebo pathway is shut down, and the clinical outcome is reduced compared to the open administration. The specific action of the drug can then be calculated as the difference between the effects in the two conditions, without the need of a placebo intervention (Amanzio et al., 2001; Colloca et al., 2004). Reconceptualizing the placebo effect as a context effect should help us shift the focus from the sugar pill to the patient, whose brain is the primary mediator of the specific physiological changes provoking the response.

The placebo response: reflex or cognitive? The early finding that a placebo effect could be reproduced in animals (Herrnstein, 1962; Ader and Cohen, 1982) suggested its interpretation as an acquired reflex, similar to the digestive reflexes of Pavlov’s dogs. Thus, the repeated co-occurrence in the patient medical history of aspects of the clinical setting associated with drug assumption (such as taste, color, shape of a tablet, as well as white coats, or the peculiar hospital smell) and therapy outcome (e.g., analgesia) can provoke what is called a conditioned response, that is, the therapy outcome induced by the clinical setting alone, in the absence of the pharmacologically active principle (Wikramasekera, 1985; Siegel, 2002; Ader, 1997). Seminal experiments were carried out in humans by Voudouris et al. (1989, 1990),

who devised a protocol whereby conditioning was achieved by pairing a placebo analgesic cream with a painful stimulation, which was surreptitiously reduced with respect to a baseline condition to make the subjects believe that the cream was effective. In this way, a direct comparison could be made between a conditioned and an unconditioned group, with the former invariably showing a larger pain reduction. This kind of protocol is still widely used today, to boost placebo effects through conditioning in the experimental setting. Although the conditioning model is too simplistic to thoroughly explain placebo effects in all situations, it has found support for physiological functions outside the conscious control, like those involving the immune system or neuroendocrine secretions (Giang et al., 1996; Goebel et al., 2002; Benedetti et al., 2003). The physiological basis for these responses can conceivably be provided by autonomic nervous system activity and the release of neuroendocrine substances from the pituitary gland, induced by the psychosocial context through neural circuits including limbic and hypothalamic relays (Ader, 2003; Pacheco-Lo´pez et al., 2006; Riether et al., 2008). When the response falls in the conscious domain, conditioning is still possible, but a dominant role is played by cognitive aspects, such as expectations, motivations, and emotions (Kirsch, 1999). Grading expectancies resulted in graded placebo effects both in experimental (Price et al., 1999) and clinical conditions (Pollo et al., 2001). The desire to achieve a goal (e.g., pain reduction) and the emotional states associated with it also contribute to determine the magnitude of placebo effect (Vase et al., 2003, 2005). Actually, the two mechanisms of conditioning and expectation are not mutually exclusive, and can act simultaneously with additive effects (Amanzio and Benedetti, 1999). It has been argued that during the conditioning process, the subject learns what to expect (Reiss, 1980; Rescorla, 1988; Montgomery and Kirsch, 1997), and in keeping with this, memory of prior experience (i.e., learning) is crucial, as demonstrated in healthy volunteers undergoing electrical painful stimulation with different conditioning protocols, who exhibited

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small, medium, or large effects, depending on previous experience and time lag between conditioning and response assessment (Colloca and Benedetti, 2006; Colloca et al., 2008a). Learning (by exposure to prior positive experience) potentiated not only behavioral (subject pain report) but also neurophysiological placebo analgesic responses, as measured by laser-evoked potentials (LEPs) after verbal suggestion of analgesia (Colloca et al., 2008b). A different cognitive mechanism, which has recently been proposed as a contributor to the genesis of placebo effects, is the recruitment of the reward circuitry. It has been argued that placebos have reward properties. Rewards are usually directed to increase survival, like food and sex, and so are the placebos with the beneficial outcome they provide. In fact, until recently, only few active treatments existed and the history of medicine largely matched that of placebo effects (de la Fuente-Ferna´ndez et al., 2004). According to this view, the expected clinical benefit is a form of reward, which triggers the placebo response (de la Fuente-Ferna´ndez and Stoessl, 2002; Lidstone and Stoessl, 2007).

Neurological disorders showing prominent placebo effects Most relevant to the neurologist are the aspects of placebo research concerning the correct evaluation of placebo effects in clinical trials and the exploitation of the surrounding clinical context to the patient’s benefit. In fact, in the search for specific brain mechanisms generating the placebo response, scientists have focused on a number of neurological disorders which represent interesting models, thanks to the known molecular dysfunctions underlying them. In particular, pain, Parkinson’s disease, and depression have been the target of recent experimental placebo research (de la FuenteFerna´ndez et al., 2002; Cavanna et al., 2007). Pain It was in the field of placebo analgesia that neuropharmacological evidence of a chemical

substrate for the placebo phenomenon was first obtained (Levine et al., 1978). Much subsequent work has corroborated the model whereby the secretion of endogenous opioids in the brain is the central event of the pain modulation by a placebo, with the activation of the descending antinociceptive pathway as its anatomical substrate (Fields and Levine, 1984; Lipman et al., 1990; Benedetti et al., 1999a, b; Pollo et al., 2003). In fact, in many of these studies, placebo analgesia was reversed by naloxone, although the presence of some naloxone-insensitive effects points to the involvement of other antinociceptive mechanisms as well, our understanding of which is still scarce (Gracely et al., 1983; Amanzio and Benedetti, 1999; Vase et al., 2005). Enhancing effects on placebo analgesia have been obtained with proglumide, a cholecystokinin (CCK) antagonist (Benedetti et al., 1995; Benedetti, 1996). It would seem that placebo analgesia is under the opposing actions of promoting endogenous opioids and inhibiting endogenous CCK, two systems which show overlapping distribution of brain receptors (Noble and Roques, 2003) and the opposing role of which has also been suggested for the emotional modulation of other incoming signals, like visual input (Gospic et al., 2008). Recently, brain imaging and mapping techniques, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), magneto-electroencephalography (MEG), and electroencephalography (EEG), have brought important contributions to the understanding of where and when is placebo analgesia generated in the central nervous system (Rainville and Duncan, 2006; Kong et al., 2007; Colloca et al., 2008). Initially, the focus was maintained on the topdown pain regulatory system already implicated by neuropharmacological studies. This endogenous opioid system has adaptive value, being called into action by fear or threat, as in stress-induced analgesia, depressing the incoming nociceptive signals (Millan, 2002; Fields, 2004). A PET study first showed that brain areas activated during opioid- or placebo-induced analgesia largely overlapped, involving part of the anatomical substrate of this system, that is, the rostral anterior cingulate cortex (rACC), the orbitofrontal cortex (OrbC),

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and the periaqueductal gray (PAG) (Petrovic et al., 2002). Subsequently, direct evidence for endogenous opioid release during a placebo intervention was provided by another PET study, measuring m-opioid receptor availability (Zubieta et al., 2005). In this study, [11C] carfentanil was displaced by the activation of opioid neurotransmission, showing significant binding decrease after placebo in pregenual rACC, insula, nucleus accumbens, and dorsolateral prefrontal cortex (DLPFC); in all areas except DLPFC, this decrease was correlated with placebo reduction of pain intensity reports. A number of other studies brought more contributions: by reporting dampened activation during placebo analgesia in brain areas of the so-called ‘‘pain matrix,’’ like thalamus, anterior insula, and caudal rACC (Wager et al., 2004; but see also Kong et al. 2006, for a contrasting report); by attempting to correlate the activation of rACC with that of the antinociceptive system, suggesting a crucial cognitive control role for rACC (Bingel et al., 2006); or by advocating a modulation by placebo of spinal activity (Matre et al., 2006; Goffaux et al., 2007). Scalp LEPs amplitude was also found to be reduced during the placebo analgesic response, namely in the N2–P2 components, thought to be originated in the bilateral insula and cingulate gyrus (Wager et al., 2006; Watson et al., 2007). As mentioned before, placebo effects can be induced by expectation of benefit even without the physical administration of a placebo. Thus, along a different line of research, knowledge of placebo analgesia can also be gained by focusing on changes in brain activity which take place during pain anticipation. In the anticipatory phase of the placebo analgesic response, increased activity in DLPFC and other frontal regions was positively correlated with increase in a midbrain region containing the PAG, and negatively correlated with the signal reduction in pain regions and with reported pain intensity. The interpretation could be that just before the onset of placebo analgesia, prefrontal cortical evaluation could drive the activation of the descending antinociceptive system (Wager et al., 2004). Similarly, a comparison of high and low expectations before a painful stimulus showed changes in

activity in many areas of the descending inhibitory pathway (Keltner et al., 2006). In order to discriminate whether expectancy exerts its psychophysical effect through changes of the perceptual sensitivity of early cortical processes [i.e., in the primary (SI) and secondary (SII) somatosensory areas] or on later evaluative elaborations, such as stimulus identification and response selection (represented in ACC), Lorenz et al. (2005) used a combined application of the high temporal resolution techniques of EEG and MEG. They found that the amplitude of the laser-evoked MEG fields in SII was highly correlated to the expected stimulus intensity as signaled by an auditory cue, while the ensuing evoked responses with source in the caudal ACC varied with stimulus intensity (requiring a varying level of task engagement) but failed to show any cue validity effects. Pain is associated with many neurological disorders, and it is hoped that a better understanding of the mechanisms underlying placebo analgesia can be reflected in the clinical practice, with clinicians sharing with experimenters the awareness of the usefulness of the placebo tool at their disposal. Parkinson’s disease and motor performance The placebo effect in Parkinson’s disease is usually obtained through the administration of an inert substance, which the patient believes to be an effective antiparkinsonian drug. The assessment of the ensuing motor performance improvement is somewhat more objective than the self-reported variation of pain, as it can be evaluated by a blinded examiner with the Unified Parkinson’s Disease Rating Scale (UPDRS). However, recent experimental work has also exploited the technique of subthalamic nucleusdeep brain stimulation (STN-DBS), manipulating the electrodes activity to configure different expectation and conditioning protocols. In an early such study, patients with the stimulator turned off showed faster hand movements when they mistakenly believed it to be on than when they were correctly informed (Pollo et al., 2002). An influence of expectation on UPDRS scores

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was also found by Mercado et al. (2006) comparing aware and unaware conditions of the stimulator status, both for the on and off situations. Thus, expectation plays an important role not only for placebo effects affecting sensory input but also for motor output. Subsequently, intraoperative recording of single neuron activity in the subthalamic nucleus in patients conditioned

with apomorphine showed that placebo responders exhibited a significant decrease of neuronal firing rate associated to a shift from bursting to a more physiological pattern of discharge. These changes were coupled to rigidity reduction and subjective reports of well-being (Benedetti et al., 2004; Fig. 1). This study demonstrated for the first time a link between a placebo intervention and

Fig. 1. The placebo effect in Parkinson’s disease patients during subthalamic nucleus (STN) electrode implantation. Correlation among arm rigidity (black circles), STN neuronal frequency discharge (shaded columns) and subjective report (italics) in the case of a placebo responder (A) and nonresponder (B). The black arrow on the abscissa indicates placebo administration. Bars represent standard deviations. The placebo responder shows a decrease in neuronal activity and arm rigidity, together with subjective improvement, all of which are absent in the placebo nonresponder. (C) Single-neuron electrical activity in the STN, before and after placebo, in a placebo responder (left and right side) and magnetic resonance image showing the STN implanted electrode (middle). Modified from Benedetti et al. (2004).

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a single cell activity, proving the influence of an expectation-inducing procedure on a specific neuronal population. In spite of the similarities with placebo analgesia, however, the neuropharmacological substrate is, in this case, quite different. In a PET study employing the D2–D3 dopamine receptor agonist [11C]raclopride as a radiotracer, de la Fuente-Ferna´ndez et al. (2001) obtained the first evidence that endogenous dopamine is released in the striatum after pharmacological placebo administration. Their finding was later corroborated by similar results obtained with the use of sham transcranial magnetic stimulation as a placebo (Strafella et al., 2006). Dopamine has been proposed as a possible mediator of placebo effects not strictly pertaining to the motor context. Its release has, in fact, been observed not only in the dorsal but also in the ventral striatum (e.g., in the nucleus accumbens), an area known to be involved in the reward circuitry (de la Fuente-Ferna´ndez et al., 2002). According to the authors, while dorsal striatum release is directly linked to performance improvement, ventral release could rather be connected to expectation of reward, that is, of clinical benefit (de la Fuente-Ferna´ndez et al., 2004). As such, it could well be implicated also in other types of placebo effect, including placebo analgesia. In fact, some of the cortical and subcortical areas activated during sustained pain are known to receive dopaminergic projections (Zubieta et al., 2001). In support of the role of reward mechanisms in generating placebo responses, Scott et al. (2007) found, in a combined PET and fMRI study, a correlation between individual responsiveness to placebo analgesia and monetary reward. The stronger the nucleus accumbens activation (fMRI) during the placebo response, the larger the dopamine release in the same nucleus during the monetary task (PET with [11C]raclopride). These results also prompt the reward system as a possible neurological substrate in the search for ‘‘placebo responders,’’ whose traits still elude research efforts (Kaptchuk et al., 2008; Oken, 2008). Finally, in a within-subject design PET study using both [11C]carfentanil and [11C]raclopride, both opioid and dopamine neurotransmission were found coupled with

the placebo response, with changes of activity induced in several brain regions associated with the opioid and dopamine networks (Scott et al., 2008). The relevance of motor placebo responses is not confined to damaged systems as in Parkinson’s disease, but it can be extended to intact motor systems. In a recent study testing ergogenic placebos, muscle performance of healthy subjects was improved and their subjective rate of perceived exertion lessened, following a conditioning and expectation-raising procedure (Pollo et al., 2008). As the subjects were required to perform leg extensions until complete exhaustion, it is tempting to speculate that the placebo effect could be exerted on a putative central governor of fatigue, which integrates peripheral and central signals to determine maximal exercise (St Clair Gibson et al., 2006). The development of rehabilitation protocols which take into account the additional instrument of placebos to stimulate ailing patients to set higher goals in their physical treatments could be an interesting development of this field. Depression Clinical trials for antidepressants show very high rates of placebo responses, with an increasing trend over time (Walsch et al., 2002). This posits a challenge for the development of new drugs, with the added complication of the subjectivity of the primary outcome measure, that is, mood rating. Imaging and brain mapping studies of placebo responses in depression have thus been stimulated by the need of physiologic indicators of treatment effectiveness. In an attempt to differentiate the therapeutic from the placebo response in patients with major depressive disorder, Leuchter et al. (2002) have used quantitative EEG to show changes in brain function of placebo responders (increase in frontal cordance) that are distinct from those associated with antidepressant medication (decrease), and from those observed in nonresponders to either placebo or medication (no change). In a PET study on the serotonin reuptake inhibitor fluoxetine, Mayberg et al. (2002) reported a pattern of activity changes (including increases in prefrontal, anterior cingulate,

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and other cortical and subcortical regions) which is similar for placebo and drug responders, with the latter exhibiting more pronounced changes. However, drug responders also showed additional subcortical and limbic variations in glucose metabolism which were not seen after placebo. Whether the serotonin system is directly affected by placebo is still a matter of speculation, as no displacement studies have yet been conducted, and long-term effects of antidepressant drugs are more difficult to study than motor or pain improvements. From research to clinical practice The importance of placebo studies for clinical practice is manifold. An initial repercussion is on clinical trial design: here, the first recommendation is to control for patient expectations as an important variable influencing trial outcome. In acupuncture studies on osteoarthritis and other acute or chronic pain conditions, group assignment (to real or sham treatment) was unrelated to effects on pain, but regrouping the subjects according to perceived group assignment resulted in significant less pain for the subjects believing to be in the real treatment group (Bausell et al., 2005; Linde et al., 2007). Similar results were obtained in a long-term study on parkinsonian patients transplanted with human embryonic dopamine neurons, in which better scores on quality of life assessment were reported by patients believing to have received the real transplant (McRae et al., 2004). A second recommendation concerns the design of clinical trials, where the employment of the open/hidden design offers the opportunity to avoid the inclusion of a placebo group, thus circumventing potential ethical limitations. Also, possible direct interactions between the drug and the patient’s expectations (i.e., the potential activation of nonspecific brain pathways by the mere act of drug administration) can be ruled out (Colloca and Benedetti, 2005). In everyday clinical practice, placebos are still widely exploited (Sherman and Hickner, 2007; Nitzan and Lichtenberg, 2008), spurring a lively ethical debate on the opportunity of their use

(Lichtenberg et al., 2004). While deception should generally be avoided, clinicians must be aware of the potential for cure of the psychosocial context. In fact, every real treatment administered has two distinct components: the active constituent and the placebo factor. Every effort should be made to enhance the latter in order to maximize the benefit of the therapeutic act. This represents a perfectly acceptable behavior, which does not challenge ethical imperatives. The patient/provider relationship is central, with both correct attitudes, skills of empathy and appropriate words on one side, and nonverbal clues intentionally or unintentionally conveyed on the other. A demonstration of the additive effect of the two components of treatment is offered by the lower analgesia obtained with hidden administration of analgesics (i.e., in the absence of psychosocial context) compared to open (Amanzio et al., 2001). Interestingly, this difference disappears in cognitively impaired patients, unable to communicate and purposefully interact with the caregiver. This loss might be taken into account when devising therapy plans for Alzheimer or other demented patients (Benedetti et al., 2006). The context influence has prompted Barrett et al. (2006) to propose a list of eight specific clinical actions: speak positively about treatments, provide encouragement, develop trust, provide reassurance, support relationships, respect uniqueness, explore values, and create ceremony. The ‘‘contextual healing’’ has been off the radar screen of scientific medicine, which has focused on therapeutic benefit produced by medical technology. We should instead redirect our attention to the wholeness of the act of administering treatment, especially for those conditions in which existing treatments are only partially effective in relieving symptoms (Miller and Kaptchuk, 2008).

Conclusions The roots of placebo effect extend into brain circuitry and biochemistry. Its mechanisms of actions are providing us with a holistic vision of mind–body interactions, enabling us to believe

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that we can influence our well-being, if not by sheer willpower, at least by employing means known to act on our central nervous system. Awareness of and feelings about treatments are able to influence patient responses both psychologically (in the mind) and physiologically (in the body), two realms no longer segregated by Cartesian dualism. Application of knowledge gained in placebo research also stretches to medical conditions outside the neurological domain, like asthma (Kemeny et al., 2007) or rheumatic diseases (Pollo and Benedetti, 2008). Results so far obtained point to the activation of specific mechanisms, with release of opioids, dopamine, hormones, immune mediators, and possibly serotonin to meet the organism need in each case. We can thus speak not of a single but many placebo effects. Whether they are triggered independently or by a common pathway is still a matter of debate. Acknowledgment This work was supported by grants from Istituto San Paolo di Torino and Regione Piemonte.

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