Fabrizio Benedetti. Placebo and the New Physiology of the Doctor-patient Relationship

8/11/2019 Fabrizio Benedetti. Placebo and the New Physiology of the Doctor-patient Relationship

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PLA EB AND THE NEW PHY I L Y F THEDOCTOR-PATIENT RELATIONSHIPFabrizio Benedetti

Department of Neuroscience, University of Turin Medical School, and National Institute of Neuroscience,Turin, Italy

LBenedetti, Fabrizio. Placebo and the New Physiology of the Doctor-Patient Relation-ship. Physiol Rev 93: 12071246, 2013; doi:10.1152/physrev.00043.2012.Modern medicine has progressed in parallel with the advancement of biochemistry,anatomy, and physiology. By using the tools of modern medicine, the physician todaycan treat and prevent a number of diseases through pharmacology, genetics, and

physical interventions. Besides this materia medica, the patients mind, cognitions, and emotionsplay a central part as well in any therapeutic outcome, as investigated by disciplines such aspsychoneuroendocrinoimmunology. This review describes recent findings that give scientific evidence

to the old tenet that patients must be both cured and cared for. In fact, we are today in a good positionto investigate complex psychological factors, like placebo effects and the doctor-patient relationship, byusing a physiological and neuroscientific approach. These intricate psychological factors can be ap-proached through biochemistry, anatomy, and physiology, thus eliminating the old dichotomy betweenbiology and psychology. This is both a biomedical and a philosophical enterprise that is changing the waywe approach and interpret medicine and human biology. In the first case, curing the disease only is notsufficient, and care of the patient is of tantamount importance. In the second case, the philosophicaldebate about the mind-body interaction can find some important answers in the study of placeboeffects. Therefore, maybe paradoxically, the placebo effect and the doctor-patient relationship can beapproached by using the same biochemical, cellular and physiological tools of the materia medica,which represents an epochal transition from general concepts such as suggestibility and power of mind

to a true physiology of the doctor-patient interaction.

I. WHAT IS A PLACEBO RESPONSE? 1207

II. WHAT IS THE DOCTOR-PATIENT... 1211

III. NEUROPHYSIOLOGICAL MECHANISMS... 1214

IV. MECHANISM-BASED CLASSIFICATION... 1219

V. DISEASE-BASED CLASSIFICATION... 1221

VI. NEW EMERGING CONCEPTS... 1234

VII. UNRAVELING PLACEBO... 1238

I. WHAT IS A PLACEBO RESPONSE?

A. Place os Were Intro uce to Vali atethe E cacy o Medical Treatments

Ancient p ysicians ave a ways use izarre an o treat-ments to cure their patients, with scarce, if any, knowledge ofanatomy and physiology. As the anatomical and physiologicadetails of both the animal and the human body started emerg-ing, the need of a scientific explanation of many medical treat-ments ecame an imperative o jective o p ysicians an t escientific community. An important historical period wherebyscientific skepticism emerged about the efficacy of some med-ical remedies is approximately in the second half of 1700 andinvolved treatments like mesmerism, perkinism, and homeop-athy (178).

To take mesmerism as an example, this was introduced in the

second half of 1700 by Franz Anton Mesmer, who claimed tohave discovered a healing fluid which he called animal magne-tism. To assess the very nature and the efficacy of mesmerism

in treatingmany iseases an symptoms, Louis XVI appointea commission t at was ea e y Benjamin Fran in. T iscommission performed what can be considered one of the first

blind assessments and sham (placebo) interventions in the his-tory of medicine. Some women were blindfolded and askewhere the mesmeric energy was being applied. As reportedby the members of the commission themselves, while the

woman was permitted to see the operation, she placed hersensations precisely in the part towards which it was directed;t at on t e ot er an , w ens e i not see t e operation, s e

placed them at hazard, and in parts very distant from thosewhich were the object of magnetism. It was natural to con-clude that these sensations, realor pretended, were determineby the imagination (133, 178). Real mesmerismwas found to

work as well as sham mesmerism in a subsequent series ofexperiments, thus leading to the conclusion that the mesmericfluid had no existence and any effect was attributable to imag-

ination.

In the same period, Elisha Perkins introduced perkinism, akind of healing procedure whereby two metal rods were

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suppose to con uct pat ogenic ui away rom t e o y.As one wit mesmerism, one o t e rst s am (p ace o)

evices in t e istory o me icine was evise y rep acingthe two metal rods with two sham wooden rods. Again, itwas found that both the metal and the wooden rods had thesame probability to induce clinical improvement (160,178), w ic in icates t at t e meta ro s a no speci ct erapeutic e ects. Li ewise, to test t e e cacy o ome-opathy, a novel therapeutic approach introduced by SamueHahnemann, whereby the belief was that a disease can becured by very small amounts of the same substances thatcause it, in the first half of 1800, bread pills (placebo) wereused by informing the patients that they were a homeo-pathic treatment (323, 178). A positive effect of bread pillswas found, and this was attributed to the natural course ofdisease and to imagination.

Many experiments and assessments of this kind were per-

formed in the following years, and they were refined moreand more over time. Physicians became aware that the out-come of many therapies was nothing more than spontane-ous remission or imagination, and they realized that rigor-ous trials were necessary to validate the efficacy of a medi-cament. The use of the word placebo (which in Latinmeans I shall please) in clinical research emerged gradu-ally over time to indicate a control group that receives asham treatment, as was done with sham mesmerism, shamro s in per inism, an s am omeopat y. T ere ore, t ewordshamwas gradually replaced with the word placebo.Another important point that was crucial for the modernuse of placebos in clinical trials was the emerging awarenessthat even physicians and clinical investigators were suscep-tible to imagination and biases. This led to the use of thedouble-blind design, in which neither the investigator northe patient knew the nature of the tested therapy (it could beeither real or sham).

With these elements in their hands, modern clinical investi-gators use t e ran omize ou e- in p ace o-contro etrial, which represents today the tenet of clinical researchor the validation of a therapy. It contains most of the

elements that are necessary to control for suggestion, imag-ination, and biases of both patient and investigator, and to

control for other confounding factors such as the spontane-ous fluctuations of diseases and symptoms.

. Today the Placebo E ect, or Response, Isan Excellent Mo el to n erstan Howthe Brain Works

Not only have placebos been used for the validation otherapies, but they have also traditionally taken as an ex-ample of the powerful interaction between mind and body.For example, in mesmerism and perkinism, the main con-clusion was that imagination played a major role in the

therapeutic outcome, thus emphasizing the important role

o min in t e mo u ation o a num er o p ysio ogicafunctions. Following this psychological perspective of theplacebo phenomenon, the placebo concept has permeatethe psychology literature for many years (76, 156, 292, 293340).

oday placebo researchers tend to use the terms placeboe ectan place o responseinterc angea y. Accor ing y,throughout this article I use these two terms as synonyms.In the course of the years, several factors have been consid-ered to be important in the placebo effect. For example,many elements are at work during a placebo response, suchas the relationship between the doctor and his patient, thepatients expectations and needs, the patients personalityand psychological state, the severity and discomfort of thesymptoms, the type of verbal instructions, the preparationc aracteristics, an t e environmenta mi ieu (281).

he importance of the mind-body interaction in the placeboeffect clearly emerges in the definition by Brody (76), whodefines the placebo effect as a change in the body, or the

ody-mind unit, that occurs as a result of the symbolicsignificance which one attributes to an event or object in thehealing environment. It is important to emphasize that thepsychological conceptualization of the placebo has beenvery important in rawing our attention on w at is rea yimportant (the meaning and the symbols of the healingenvironment), and deflecting it from what is not (the inertme ica treatments) (239, 240). T ere ore, w ereas in t eclinical trial setting the conceptualization of placebo fo-

cuses on distal and external factors, such as inert treat-ments an inert su stances, in t e context o psyc o ogythe concept of placebo focalizes on proximal, and inter-nal, factors, like symbolic representation and mind-bodyrelationship (269).

he merits of the psychological conceptualization of theplacebo effect as a mind-body phenomenon reside in thefact that it makes us understand that the placebo effect isdue to the psychosocial context around the patient and thetherapy. When a placebo (sham treatment), e.g., an inertsubstance like water, is administered, what matters is notthe water, of course, but its symbolic significance, whichcan be attached to practically anything (76). In this sense,the concept of placebo has shifted from the inert contentof the placebo agent to the concept of a simulation of anactive therapy within a psychosocial context.

On the basis of these considerations, when a treatment isiven to a patient, be it sham or real, it is not administered

in a vacuum, but in a complex set of psychological statesthat vary from patient to patient and from situation tosituation. For example, when a placebo is given to relievepain, it is administered along with a complex set of psycho-social stimuli which tell the patient that a clinical improve-

ment should be occurring shortly FIGURE 1. These psycho-

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social stimuli represent the context around the therapy andthe patient, and such a context may be as important as thespecific effect of a drug. The contextual factors that mightaffect the therapeutic outcome can be represented by thecharacteristics of the treatment (color and shape of a pill),the patients and providers characteristics (treatment and

i ness e ie s, status, sex), t e patient-provi er re ations ip(suggestion, reassurance, and compassion), the healthcaresetting (home or hospital, and room layout) (103). Thus thecontext is made up of anything which surrounds the patientunder treatment, like doctors, nurses, hospitals, syringes,pills, and machines FIGURE 1 , but certainly doctors,nurses, and health professionals represent a very importantcomponent of the context, as they can transmit a lot ofinformation to the patient through their words, attitudes,and behaviors (41). Balint (27) called this context the wholeatmosphere around the treatment.

This line of reasoning paved the way for the neuroscientificinvestigation of the placebo response. Starting from the firstbiological investigations of the placebo effect, for example,in the early 1960s in animals (169) and in the late 1970s in

umans (212), to ay p ace o researc is a comp ex e oinvestigation which ranges from psychology to psychophys-iology, from pharmacology to neurophysiology, and fromcellular/molecular analysis to modern neuroimaging tech-n ques.

What neuroscientists have learned from the psychologicaland social approach is that placebos are not inert sub-stances. Instead, they are constituted of different words and

therapeutic rituals as well as of different symbolic elements

which, in turn, can influence the patients brain; thus theyare amenable to classic neuroscientific investigation. Neu-roscientists use the placebo response as a model to under-stand how our brain works, and indeed, it is emerging as anexcellent approach to understand several higher brain func-tions, such as expectation and reward. The placebo re-

sponse is to ay a me ting pot o i eas or neuroscience. Infact, there is not a single but many placebo effects, and thereis not a single but many mechanisms across different con-ditions and interventions (43, 44, 119). In fact, sometimesanxiety mechanisms are involved, whereas reward mecha-nisms are involved in other circumstances. Likewise, differ-ent types of learning and genetic variants may be important.

C. Appropriate Controls Are Necessary toRule Out Other Phenomena

Not all improvements observed after placebo administra-

tion are attributable to real psychobiological phenomena.In fact, many improvements can be due to different factors,such as the natural history of the disease, regression to themean, iases y experimenters an patients, as we as un-i entifie cointerventions FIGURE 2 . Therefore, the pla-

ebo effect is approached differently by the clinical trialistand the neuroscientist, because the former is not interestein the cause of the improvement following the administra-ion of the inert substance, whereas the latter is intereste

only in the psychobiological factors that lead to the im-provement.

In pragmatic clinical trials, the trialist only needs to establish

whether the true treatment is better than a placebo, regardless

Sight of

health professionals,

hospitals andmedical instruments

Interaction with otherpatients and people

Touched by needlesand other devices

Color, shape, smell

and taste of

medications

Words by

doctors andmedical personnel

Personal beliefsand expectations

Memories aboutprevious therapies

FI URE 1. e psyc osoc a context aroun t e pat ent an t e t erapy. en a me ca treatment s

administered, several sensory and social stimuli, as well as personal beliefs and memories, tell the patient that

a therapy is being performed. The whole context constitutes the ritual of the therapeutic act, which is at the

very heart of placebo and nocebo responses.

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of the causes behind the placebo improvement. Although thispragmatic approach is useful in clinical trials, if one is inter-ested in the mechanisms of the real psychobiological placeboeffect, it is necessary to separate it from other phenomena suchas spontaneous remission, regression to the mean, biases (43,44). For example, spontaneous remission is frequently anerroneously defined placebo effect. In fact, in many chronicconditions there is a spontaneous variation in symptom inten-sity that is known as natural history (128). If a subject takes a

p ace o just e ore is symptom starts ecreasing, one maybelieve that the placebo is effective, although that decreasewould have occurred anyway. Clearly, this is not a placeboeffect but a misinterpretation of the cause-effect relationship.To avoid this mistake, the natural history must be comparedwith a placebo treatment andan active treatment. Whereas thedifference between the natural history and the placebo treat-ment represents the real psychological placebo component ofthe therapy, the difference between the placebo treatment andthe active treatment represents the specific component of thetherapy.

Similarly, regression to the mean is a statistical phenome-non that is often misinterpreted as a psychological placeboresponse. It assumes that individuals tend to have extremevalues of a physiological parameter, e.g., glucose, whenenro e in a c inica tria , an t en t ese extreme va uestend to be lower at a second measurement (97). In this casealso, the improvement cannot be attributed to any interven-tion they might have undergone. An important factor in theregression to the mean phenomenon is represented by theinc usion criteria in a c inica tria , w ic are o ten repre-sented by extreme physiological values.

Signal detection ambiguity can sometimes explain symptom

reduction. In fact, according to the signal detection theory,

a false-positive error made by either the patient or the phy-sician may explain the illusory improvement occurring insome circumstances (12, 86). Likewise, sometimes patientsand doctors give biased reports of the clinical condition. Forexample, there is some evidence that patients often want toplease doctors for their time and effort to help them so thatsome exaggeration of their feelings of clinical improvementmay be reported (184). This can be overcome by usingobjective measurements, such as electrophysiological re-

sponses or oo mar ers. Fina y, cointerventions cansometimes be the cause of improvement. For example, anunidentified concomitant diet may be responsible for theclinical improvement during a placebo treatment.

For all these reasons, classical clinical trials are not good forunderstanding the mechanisms of real psychological pla-cebo effects, for all these phenomena are present in a clinicaltrial. As the context surrounding the patient and the therapyis the crucial factor in placebo responsiveness, and psycho-logical factors are at the core of its magnitude, we shouldnot be surprised that placebo effects in clinical trials are

highly variable. Again, this emphasizes the usefulness of theneuroscientific approach in the laboratory setting to clarifythe biology of different placebo responses, for in the labo-ratory it is possible to manipulate the context and the pa-tients psyc o ogica state un er strict y contro e con i-ions.

D. The Nocebo Effect Is the Opposite of thelace o Effect

Nocebos are opposite to placebo phenomena, for they in-volve the pathogenic effects of imagination and negative

expectations. Nocebo phenomena were first described

Co-interventions

Placebo(sham treatment)

Natural

history

Regression

to the mean

Experimenters

and patients biases

Psychobiological

factors

Clinical Improvement

FI RE 2. The clinical improvement that may be observed after placebo administration is due to manyfactors. The real placebo response is attributable only to the psychobiological factors, namely, to psychologicalan p ys o o g ca c anges n t e pat ent s ra n.

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wit in an ant ropo ogica context in tri a societies, anta en as a goo examp e o t e power o min . For exam-p e, in some a origina peop e o Austra ia, pointing a oneat someone may lead to negative outcomes, and in LatinAmerica and Africa, voodoo death has sometimes been re-lated to the belief of being bewitched (79). It should beemp asize t at many o t ese p enomena are anec ota(215); nonet e ess, t ey can e exp aine as a stress-in-duced activation of the sympathetic nervous system (79).Some anthropologists go further by proposing a sociocul-tural model of illness and healing, whereby placebos andnocebos are crucially involved (152, 153).

Nocebo phenomena and the impact of negative expecta-tions and imagination are not limited to the past and totribal societies, but they are also present in western societ-ies. For example, many side effects both in clinical trials andin clinical practice are psychological, and many health

warnings by the media may induce negative expectationsand negative outcomes (18, 244, 277). Similarly, anticipa-tory nausea and vomiting in cancer chemotherapy, the neg-ative effects of negative diagnoses, and patients distrusttowards conventional medicine, all represent examples onocebo and nocebo-like phenomena in western societies(159, 309)

The term noce o(Latin I shall harm) was introduced toescri e t e negative e ects o p ace os (259). However, it

is important to stress that in modern terminology true no-cebo effects are considered as the result of negative expec-tations. This conceptualization of nocebo effects is particu-larly useful from a neuroscientific perspective, because no-cebo administration induces negative expectations andthese, in turn, are anxiogenic. In other words, a nocebo is astressor. Therefore, the nocebo response is a good model tounderstand anxiety, particularly anticipatory anxiety.

Not surprisingly, our knowledge about the mechanisms ot e noce o response sti ags e in t e more etai e un-derstanding of the placebo counterpart, mainly due to eth-ical constraints. Inducing negative expectations and inflict-ing pain is certainly unethical; thus many studies are carrieout on healthy volunteers rather than on patients, and neg-

ative expectations are triggered without actual administra-tion of any substance (61, 90).

II. WHAT IS THE DOCTOR-PATIENTRELATIONSHIP?

Different disciplines have approached the doctor-patientrelationship, often also labeled patient-provider interactionor therapist-patient encounter, from different perspectives,including psychology, sociology, philosophy, and healthpolicy. What has emerged in the course of the years is thatnot only should health professionals learn technical skills,

but they also should develop appropriate social skills to

etter interact an communicate wit t eir patients. Witt e recenta vanceso neuroscience, to aywe are in a etterposition to approach the doctor-patient relationship from a

iological perspective and to consider it as a special type osocial interaction. Indeed, this new biological approach isquite interesting because the neurosciences are interested inun erstan ing ow rains wor , an t is specia socia en-counter may uncover the mechanisms of higher brain func-tions, such as expectations, beliefs, trust, hope, empathy,and compassion. In addition, since any biological system isa product of evolution which has emerged in animals andhumans with a precise purpose, an evolutionary under-standing of why and how these social mechanisms haveemerged and evolved is of paramount importance, for they

ive us insights into the relationship between the first socialinteractions in non-human primates and early hominidsand subsequent medical care.

. The Doctor-Patient Relationship Hasmerge ur ng vo ut on as a n queocial Interaction

Many simple behavioral repertoires are aimed at protectingthe body from possible damage. For example, the with-drawal reflex and the scratch reflex protect from threaten-ing stimuli, and they are present in both invertebrates andvertebrates, including humans. However, from an evolu-tionary perspective, the two reflexes differ for at least oneimportant aspect. In fact, the scratch reflex is particularlyinteresting because, differently from the withdrawal reflex,

t e movement is aime at targeting t e potentia noxiousstimulus and at removing it from the body. This representsan important evolutionary step toward the more complex

ehavior of grooming, which involves behaviors such asscratching, licking, preening, rubbing, nibbling, and wal-lowing (46). Interestingly, whereas the scratch reflex is trig-

ered by cutaneous stimuli, such as a bugs bite, grooming isa self-directed behavior that does not require the peripheralstimulation of the skin, for its biological function is the careof the body surface (49, 304). The more complex functionof grooming is also evidenced by the involvement of su-praspinal centers, whilst the scratch reflex only requires the

spinal cord. The evolutionary step from the peripherallydriven scratch reflex to the centrally driven grooming be-havior shows how the nervous system developed from asimple reflex act to a complex motor pattern for the care ot e w o e o y sur ace.

But the big evolutionary jump to social behavior is repre-sented by allogrooming, i.e., taking care of the skin of oth-ers. In fact, not only do animals scratch, rub, and lick them-se ves, ut t ey scratc an ru t eir companions as we .Social grooming has a function in the regulation of sociarelationships, and it is not only involved in the care of bodysurface (304). Individuals who are virtually free of parasites

still solicit for and submit themselves to being groomed.




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A ogrooming time corre ates wit socia group size, w icsuggests that it has to do with intense social relationships(109). In contrast to scratch reflexes and self-grooming,which require neuronal circuits in the spinal cord and in thebrain stem, respectively, allogrooming is related to the ce-

rebral cortex.

Two actors ta e part in socia grooming: t e one einggroomed and the groomer. Whereas the former benefitsfrom it in a number of ways, such as the pleasure, relax-ation, and hygiene induced by touch, it is less clear what the

enefits are for the latter. Since there are no imme iatebenefits to the groomer, for he spends energies and time tothe advantage of others, the act of grooming can be consid-ered an early form of altruistic behavior such as reciprocalaltruism. In fact, the roles of the groomer and the groomeeare re ate , ecause any in ivi ua can e eit er a groomeror a groomee. Therefore, if there is no immediate advantage

to the groomer, the service can be returned by the one whois eing groome . Reciproca a truism exp ains cases o a -truism among nonkin organisms (322).

From social grooming, prosocial behavior in early hominidsevolved in a number of ways. One of these was the care othe weak, the sick, the elderly and, more in general, thein ivi ua w o nee s e p. For examp e, tosurvive in arsconditions, it was crucial for our ancestors to obtain a dailynutritious diet of meat and other food. However, this dailyprovision was not guaranteed, because of the high variabil-ity of hunting success. Although the first altruistic ex-

changes were likely to occur among relatives, thus boost-ing kin selection, subsequently further food exchangesoccurred with nonkin that were less lucky on that partic-ular hunting day. According to the reciprocal altruismmechanism, these nonkin recipients eventually returnedthis favor (326).

There are many examples of early forms of compassion,such as a toothless skull dating back 1.7 million years thatwas found in the site of Dmanisi in the Eurasian Republic ofGeorgia, suggesting that companions might have helpedhim in finding soft plant food and hammering raw meatwith stone tools (222). Similarly, Neanderthal men havebeen found to show signs of compassion towards their com-panions, dating back to about 60,000 years ago. For exam-ple, the analysis of undeveloped bone structure indicatesthat a man at Shanidar caves was a severe cripple frombirth. His right upper limb was entirely useless and exten-sive one scar tissue in icate that he was lin in his lefteye. These extensive lesions suggest that he was apparentlycared for by his companions until his death at age 40, whichrepresents a very old age by Neanderthal standards (343).

A t oug in ear y omini s t ese a truistic acts were a -opted by different members of the group, in the course of

evolution a single member of the group assumed the role of

t e person w o ta es care o t e sic , name y, t e s aman.Pre istoric s amanism represents t e rst examp e o me -ical care, which is characterized by a good relationship be-tween the sick and the shaman. The sick trusts the shamanand believes in his therapeutic capabilities; thus he refers tohim for any psychological, spiritual, or physical discomfort.In t is way, t e s aman acquire a more an more centrarole and a higher social status in any social group acrossdifferent cultures. While shamanistic procedures are mainly

ased on religious beliefs and the supernatural origin odiseases, several rational treatments emerged over the cen-turies. For example, a broken arm or leg was covered inriver clay or mud and the cast allowed to dry hard in thesun, animal skin was used for bandages, and surgical pro-cedures, such as skull trepanning, were carried out. Thetransition from shamans to modern doctors is recent anddepended on the emergence of modern scientific methodol-ogy.

B. Four Different Steps Can Be Identified

he advantage to approach the doctor-patient relationshipfrom an evolutionary perspective consists of consideringthis special interaction as a social/biological characteristicof mankind. It has evolved from grooming to social groom-ing, and hence to the emotional concern for the sick. Sincesome biological mechanisms of self-grooming and socia

rooming are partially understood, it is natural to broadenour biological knowledge to more complex forms of sociainteraction, such as the interaction between the healer an

is patient. From a p ysio ogica an neuroscienti c per-spective, the whole process of the doctor-patient encountercan be subdivided into at least four steps (46) FIGURE 3.

he first is the step of feeling sick, a crucial starting pointhat triggers the subsequent behavior. Physiology and neu-

roscience have a lot to say about feeling sick, for it involvessensory systems that convey different pieces of informationrelated to peripheral organs and apparatuses, as well asbrain regions that lead to conscious awareness. For exam-ple, the perception of a symptom such as pain is the productof bottom-up processes taking place in the peripheral and

entral nervous system and of top-down modulation fromognitive/evaluative and emotional/motivational brain ar-eas. The second step is what makes a patient seek relief, a

ind of motivated behavior that is aimed at suppressingiscom ort. T is e aviora repertoire is not i erent rom

hat aimed at suppressing hunger or thirst, and the brainreward mechanisms are crucial in this regard. These firstwo steps are the key elements that lead the patient to looor a healer/doctor who himself represents a powerful re-

war (46).

he third step is when the patient meets the therapist,a special and unique social interaction in which the ther-

apist represents the means to suppress discomfort. Here

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many intricate mechanisms are at work, such as trust andhope on the one hand and empathy and compassion onthe other. Physiology and neuroscience are beginning tounderstand these complex functions both in the patientsbrain, where expectations, beliefs, trust, and hope arekey elements, and in the doctors brain, in which em-pathic and compassionate behavior represents an essen-tial factor. Finally, the fourth step is when the patientreceives the therapy, the final and perhaps the mostimportant act of the doctor-patient interaction. The mereritual of the therapeutic act may generate therapeutic

responses t roug t e patients expectations an e ie s(placebo responses), which sometimes may be as power-ful as those generated by real medical treatments. Today,these placebo responses can be approached from a bio-logical perspective, whereby the biochemical, anatomi-cal, and physiological link between expectation and ther-apeutic effect has been partially unraveled.

It can be seen in FI RE that these four steps can beconceived as a homeostatic system in all respects. Thefeeling of sickness is the variable to be controlled. It tellsa motivational system to seek relief. This is aimed at

adopting the appropriate behavioral repertoire to elimi-nate the feeling of sickness. In a social group, such abehavioral repertoire is represented by the social contactwith the healer, whose role is to administer a relievingtreatment. It is crucia to un erstan t at t is system isalways at work, regardless of whether the healer admin-isters effective or ineffective therapies. Even if the ther-apy is totally ineffective, the patients expectation of ben-efit (the placebo response) may be sufficient to inhibit

iscom ort. T e rea i erence etween s amans anmodern doctors is that, whereas shamanic procedures arelikely to lack specific effects completely, at least in mostcircumstances, modern doctors rely on effective proce-

dures and medications with specific mechanisms of ac-

ion. But this social-neural system is always there, as anancestral system which is ready to come out, both withshamans and with modern doctors.

. What Is the Link Between Place o anDoctor-Patient Relationship?

If we look at FIGURES 1 AND , the link between placeboand doctor-patient interaction appears straightforward.

he main element in the psychosocial context around thepatient that leads to the placebo response is the doctor,and more in general the health professional. Indeed, anyelement in FI RE 1is related to the figure of the doctor,who uses communication, words, and medical instru-ments and administers pills, injections, and medications(41, 67). Likewise, the behavioral repertoire that is ad-opted by the patient inFI RE is aimed at looking for adoctor, who represents the means for relieving discom-ort. Therefore, it is not surprising that a crucial element

that triggers the placebo response comes from the veryspecial social encounter between the patient and his doc-or. In FIGURE 3, the crucial steps that need to be ana-yzed in depth are the third (meeting the therapist) an

the fourth (receiving the therapy). It is here that a newphysiology of the doctor-patient relationship and pla-ce o oes emerge. Meeting t e octor invo ves p enty omechanisms in the patients brain that are responsible forexpectations, trust, and hope. Similarly, many mecha-nisms are at work in the doctors brain, such as empathyand compassion. In turn, these lead to the final step ofreceiving the therapy which, regardless of its effective-ness or ineffectiveness, triggers placebo responses. Thephysiological underpinnings of the third and fourtsteps o FIGURE are described in depth in the next

sections.

FEELING SICK

Bottom-up processing (sensory afferents)

Top-down modulation (psychological influences)

SEEKING RELIEF

Motivation to suppress discomfort

Reward mechanisms

RECEIVING THE THERAPY

Placebo and nocebo mechanisms

Brain changes induced by therapeutic ritualsMechanisms of expectation and learning

MEETING THE THERAPIST

The doctors brain (empathy and compassion)

The patients brain (trust and hope)

1 2

34

+

+

+-

he four steps of the doctor-patient relationship. The interaction between the healer/therapistand his patient can be envisaged as a homeostatic system in which the variable to be controlled is represente

by the feeling of sickness (symptoms). The very act of administering a treatment is a psychological and socia

event that is sometimes capable of inhibiting a symptom such as pain, even though the treatment is fake.




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III. NEUR PHY I L I AL ME HANI MNV LVED IN THE INTERA TI N

BETWEEN D T R AND PATIEN

A. Exploring the Healers and the

Doctors Brain

As the main components of the psychosocial contextaround the patient, the doctors words, attitudes, and be-haviors play a major role in the doctor-patient interactionand in the placebo responses. As briefly described above,altruism, empathy, and compassionate behavior emerged inmankind during the course of evolution, and the shamanassumed the role of caregiver. It is interesting to note thatfacial expressions are likely to have evolved for elicitingmedical attention from others (345). A greater facial ex-pression of pain in the presence of potential caregivers than

in their absence is of primary importance, so that the pres-ence of potential caregivers would prompt the release ofsuppression of pain facial expressions. This, in turn, triggersthe caregivers empathic and compassionate behavior. Thesocia connection etween t e su ering patient, w o ex-presses his discomfort, and the empathic doctor is at thevery heart of the doctor-patient relationship. Empathy thusrefers to an intersubjective process through which the cog-nitive and emotional experiences of another come to bes are , wit out osing sig t o t e origina source o t eexperience (102). It is important to note that empathy isdistinguished from compassion (32, 117, 161). Empathy isnot necessarily linked to prosocial motivation, namely, the

concern about the others well being. In contrast, prosociamotivation is involved in compassion. In fact, compassionenables individuals to enter into and maintain relationshipsof caring and tends to motivate us to help people who areemotionally suffering. In the next sections, empathy andcompassion will be treated separately, for different neuralsystems are involved in these behaviors.

1. There are two different neural systemsfor empathy

Experimental evidence suggests that there are at least two

mechanisms of empathy: emotional contagion and cognitiveperspective-taking (101). Whereas the former is thought tosupport our ability to empathize emotionally, i.e., to share theother persons emotional feelings (I feel what you feel), theatter invo ves comp ex cognitive components, w ere y one

infers the state of the other person (I understand what youfeel), also known as theory of mind (266), or mentalizing(136), or mindreading (29).

Severa stu ies suggest t at un erstan ing ot ers on t ebasis of cognitive perspective taking and emotional conta-gion recruits different neural networks (161). FI RE 4shows the two main systems that mediate empathic emo-

tional ability on the one hand (light blue) and cognitive

perspective taking on the other (blue). Whereas cognitiveperspective taking activates the medial prefrontal regions,the superior temporal sulcus, the temporal pole, and thetemporo-parietal junction (135, 283), empathizing with an-other person has been found to activate somatosensory aninsular cortices as well as the anterior cingulate cortex(161). In a study by Singer et al. (296), the bilateral anterior

insula and the rostral anterior cingulate cortex were acti-

Lateralhemisphere

Medialhemisphere

Cognitive perspective taking

ACC

iFG

MFC

TP

TPJ

vmPF

STSAI

SII

asPM

C

piPMC

Empathic emotional ability

Compassion for physical pain and admiration for skills

Compassion for social pain and admiration for vir tue

FIGURE 4. ran reg ons t at are nvove n empat y, compas-

sion, and admiration. During the doctor-patient relationship, severa

complex brain functions are involved, such as the doctors empathic

an compass onate e avor an t e pat ent s a m rat on trust to-

wards the figure of the doctor. iFG, inferior frontal gyrus; AI, anterior

insula; SII, secondary somatosensory area; TP, temporal pole; STS,superior temporal sulcus; TPJ, temporal parietal junction; MFC,

medial rontal cortex; vmPF, ventromedial pre rontal cortex; A ,

anterior cingulate cortex; asPMC, anterosuperior posteromediacortex; piPMC, posteroinferior posteromedial cortex.

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vate w en a ema e experience pain erse as we aswhen she saw that her husband had experienced pain. Thesame group (297) showed that the empathic brain responsesin the anterior insula and anterior cingulate cortex were notrestricted to a beloved partner, but also occurred when anunknown but likable person was in pain, which has obviousimplications for the doctor-patient interaction.

The involvement of other regions was demonstrated in sub-jects with lesions either in the ventromedial prefrontal cor-tex or in the inferior frontal gyrus. In fact, a remarkable

ehavioral an anatomic ou le issociation etween ef-icits in cognitive empat y (ventrome ia pre ronta esion)and emotional empathy (inferior frontal gyrus lesion) wasfound (291) FIGURE 4.

While pain is surely the modality that has been investigatedin more detail, similar empathic responses have also been

described in other modalities, like touch, taste, and disgust.For examp e, ot o servation o touc an rst- an ex-perience of touch activate the secondary somatosensorycortex (182), and video clips showing people samplingpleasant and unpleasant tastes make observers experiencethe same tastes, along with activation in anterior insulacortex when both observing and experiencing disgust (174).

2. Compassion for social and physical pain involvestwo discrete neural systems

Compassion can be evoked by witnessing situations of per-

sonal loss and social deprivation (social pain), or by wit-nessing bodily injury (physical pain). Whereas the formerpertains to social/psychological circumstances, the latter

as to o wit imme iate p ysica circumstances (173).Compassion for social and physical pain has been found toengage two different neural circuits. The former is associ-ated with strong activation in the inferior/posterior portionof the posteromedial cortices, whereas the latter produced alarger activation in the superior/anterior portion of the pos-teromedial cortices (173) FIGURE 4 . These neural net-works, one for the emotions related to someone elses psy-chological state and the other for the emotions related to

someone elses physical state, are engaged by both compas-sion and admiration (see below).

It is interesting to note that compassionate concern towardsa suffering person is related to the motivation to help and,accordingly, a positive intrinsic reward feeling may occur asa result of experiencing compassion for others (303). In-deed, Kim et al. (185) found that compassionate attitudeactivated a neural network in the midbrain/ventral stria-tum/septal network region, a key region involved in proso-cial/social approach motivation and reward mechanisms.These findings emphasize the differences between empathicbehavior, which does not necessarily involve motivational

systems, and compassionate behavior, whereby the motiva-

ion to a eviate ot ers su ering represents t e centra e e-ment.

. Doctors can habituate to others suffering

here is some experimental evidence that habituation toothers suffering occurs in clinical practice. This may haveevolved as a mechanism of self-control that is aimed atreducing negative emotions while doctors watch the suffer-ing of their patients. This may be particularly true for those

ea t pro essiona s invo ve in invasive an pain u proce-dures. Indeed, Cheng et al. (83) conducted a functionamagnetic resonance imaging study, in which they comparedphysicians who practice acupuncture with naive partici-pants (contro s) w i e o serving t e insertion o nee esinto t e mout area, t e an s, an t e eet. T e anteriorinsula, somatosensory cortex, periaqueductal gray, and an-erior cingulate cortex were significantly activated in the

ontrol group, whereas the group of acupuncturist physi-ians did not show significant changes. The latter showed

activation of the medial and superior prefrontal corticesand the temporoparietal junction, which are known to beinvolved in emotion regulation. The difference in brain ac-ivation between the two groups of naive and expert sub-

jects is likely to reflect top-down processes related to pastexperience and practice with acupuncture.

B. Different Sensory Systems Are at WorkDuring the Doctor-Patient Interaction

Needless to say, the auditory/language systems play a criti-cal role in the doctor-patient relationship, for verbal com-munication represents one of the most important social in-teractions between therapists and their patients. The doc-tors words and sentences may have a profound impact onthe patients psychological state. For example, some subtledifferences in verbal communication may produce differenteffects. There is compelling evidence that different sen-tencessuc as T is pain i ermaywor orRestassure ,t is pain i er oes wor may ea to i erent t erapeuticoutcomes (41, 44). Besides this powerful verbal communi-cation, there are a number of sensory inputs that represent

the basis of nonverbal communication, most notably visionan touch.

1. Visual stimuli are crucial innonverbal communication

Facial expressions represent an excellent source of informa-tion and play a fundamental role in signaling social inten-tions from which people infer meaning (134). Several brainregions are involved in detecting subtle differences in faciaexpressions, and these regions make up a complex networwhich is specifically aimed at processing facial emotions,whereas facial identity is processed by a different network

(319). The specialness of face processing is shown by the




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act t at even a sp it-secon g impse o a persons ace te sus is/ er i entity, sex, moo , age, race, an irection oattention (324). In uman rain imaging stu ies, a num erof works support the idea that the lateral side of the rightmid-fusiform gyrus, the fusiform face area or FFA, isactivated robustly and specifically by faces (177, 324). Its ou e note , owever, t at t e usi orm ace area oesnot respon on y to ace stimu i ut a so to non- ace o ject,albeit less robustly. The information that is gained fromfaces is fundamental for social interaction, including thedoctor-patient encounter, and some more details will bepresented in section IIIC1.

Eye contact, i.e., the mutual eye gaze that connects peopletogether, represents another important aspect of social in-teraction and solicits attention and interest of the interact-ing persons (290). Differently from other animals, wherebyeye contact may represent a potential threat (118), in hu-

mans mutual eye gaze triggers attention and interest. Atleast five regions have been found to be activated more bydirect gaze than by averted gaze: the fusiform gyrus (orfusiform face area), the anterior part of the right superiortemporal sulcus, the posterior part of right superior tempo-ral sulcus, the medial prefrontal cortex and orbitofrontalcortex, and the amygdala (290). These regions may be ac-tivated by direct gaze through different mechanisms, sucas the activation of the arousal system (179), the activationo a communicative intention etector (135), an t e acti-vation of a subcortical face detection pathway (290).

Gestures and postures represent another important aspectof social interactions. The perceived behavior of others af-fects ones own behavior unconsciously. For example, peo-ple are likely to rub their face if their conversation partnerdoes so (81). When observing the gestures of others, one caninfer his intentions and, accordingly, adapt his own behav-ior. Mirror neurons are at the very heart of this social be-havior and play a critical role whenever the behavior oot ers is o serve (279).

Nonverbal communication, as briefly described here fromfacial expressions to eye contact and from the observationof others gestures to guessing the others intentions, is crit-

ical in any social encounter, including the special situationof the doctor-patient interaction. Nonverbal messages anintentions can be communicated either consciously or un-consciously to others, and indeed gestural communicationmay have represented a primitive form of language, as sug-gested by some (278).

2. Emotionally meaningful tactile stimuli can makepain more bearable

Touch may convey strong emotional information in manycircumstances. For example, in section IIA we have seenthat social grooming is an important mediator of social

relationships in nonhuman primates. The very act of

rooming, scratc ing, ru ing, an ic ing anot er mem-er o t e same socia group is a comp ex concertation o

neura events t atta e p ace in ot cortica an su corticaareas. In humans, a powerful emotional tactile stimulus isrepresented by hand-holding, which can be considered anonverbal supportive social behavior in all respects. A studyinvestigating t e io ogica e ectso an - o ingwas per-orme onmarrie women w o weresu jecte tot e t reat

of electric shock in three different conditions: while holdingtheir husbands hand, while holding the hand of an anony-mous male experimenter, or holding no hand at all (87).Holding the spouses hand produced a decrease in unpleas-antness ratings compared with no hand-holding, whilstholding the strangers hand did not decrease unpleasant-ness. Functional magnetic resonance imaging showed re-duced activation in right dorsolateral prefrontal cortex, leftcaudate-nucleus accumbens, and superior colliculus whenhe women held their husbands hand. All these areas are

related to emotional and behavioral threat responses. Amore limited reduction of activation occurred when theyheld the hand of a stranger, e.g., in the ventral anteriorcingulate cortex, posterior cingulated and right postcentral

yrus. It is interesting to note that these effects of spousalhand-holding were related to marital quality: the higher themarital quality, the lesser the activation in the right anteriorinsula, superior frontal gyrus, and hypothalamus duringspouse hand-holding, but not during stranger hand-hold-ing.

C. Exploring the Patients Brain

On the basis of the healers/doctors words, attitudes, anehaviors, several cognitive and emotional mechanisms are

activate in t e rain o t e sic , suc as t ose invo ve incomplex functions like trust and hope. These, in turn, leato expectations and beliefs, which represent some of theprincipal elements involved in the placebo responses, whichwill be treated starting from section IV.

1. Trustworthiness decisions involve the amygdalaand oxytocin

rust can be conceptualized as a set of beliefs that the ther-apist will behave in a certain way (316). Patients usuallyase their trust on the therapists competence, compassion,

confidentiality, reliability, and communication (254). Pa-tients trust in t eir p ysicians as a ways een consi ereas an important element that per se may have beneficiaeffects on the overall health status. This may occur througa better adherence to treatments as well as the reinforce-ment of clinical relationship and patient satisfaction (254).

Deciding if an unfamiliar person is trustworthy representsone of the most important decisions in everyday life. Eithera good or a bad interaction very much depends on this

decision. One hundred milliseconds of exposure to a neutral

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ace is su cient or t is comp ex tas (346). T is very s ortperiod of time shows that face exploration is not necessaryfor trustworthiness judgments, for a time lag of 100 ms isnot sufficient for exploratory saccadic eye movements(319).

Patients with amygdala damage show an impairment inrecognizing emotiona acia expressions (8, 9, 78, 352). Inparticular, patients with bilateral amygdala lesion show abias to perceive untrustworthy faces as trustworthy (8). Adissociation between processing of face evaluation and fa-cial identity has been found. There are prosopagnosic pa-tients who can recognize emotional expressions but notidentity (68, 95, 108, 321). Likewise, there is some evidencethat individuals with developmental prosopagnosia canmake normal trustworthiness judgments but show im-paire perception o ace i entity (319).

Besides these lesion studies, there is accumulating evidenceon the role of the amygdala in trustworthiness judgementsthat comes from imaging studies. For example, in one study,subjects were asked to make either explicit or implicit trust-worthiness judgments of unfamiliar faces. It was foundthat, regardless of the task, the amygdala activity increasein relation to subjective untrustworthiness, whereas therig t superior tempora su cus activity increase on y ur-ing explicit trustworthiness judgments. Thus the automaticengagement of the amygdala and the intentional engage-ment of the superior temporal sulcus are dissociated (348).In a different study, it was found that the amygdala re-

sponse to faces increased as the untrustworthiness of thefaces increased (121), thus supporting the notion that theamygdala automatically categorizes faces according to per-ceived untrustworthiness.

Trust behavior has been found to undergo hormonal mod-ulation by oxytocin. This hormone is known to have proso-cial effects in humans, like the modulation of social inter-action behavior and social cognition (31, 163) and the in-fluence on a persons ability to infer anothers mental state(107). In addition, couples receiving intranasal oxytocinprior to a videotaped conflict discussion show an increasein positive communication behaviors (105). Oxytocin hasalso been found to strengthen the anxiolytic effect of thepresence of a friend during public speaking (162). Geneticvariants of the serotonin transporter (5-HTT SLC6A4 poly-morphism) and the oxytocin receptor (OXTR rs53576polymorphism) have been studied in different populations.For example, mothers with these two polymorphismspresent lower levels of sensitive responsiveness to theirchildren (26).

One of the prosocial behaviors that is affected by oxytocinis trustwort y e avior. An increase in p asma oxytocinwas found in subjects who participated in a trust game

whereby cooperative behavior can benefit both parties

(353). In a i erent stu y, it was oun t at in a trust gamet e intranasa a ministration o oxytocin was associatewith a larger amount of money given by an investor to atrustee (197). Interestingly, oxytocin receptors are abun-dant in the amygdala (171). The neural circuitry of trust-worthy behavior was studied by combining the intranasala ministration o oxytocin wit unctiona magnetic reso-nance imaging (35). The investigators found that oxytocininduced no change in trusting behavior after the subjectslearned that their trust had been breached several times,while the control subjects who had not received oxytocindecreased their trust. This difference in trust adaptation wasassociated with a reduced activation in the amygdala, themidbrain regions, and the dorsal striatum in subjects receiv-ing oxytocin.

aken together, the findings on the amygdala and oxytocinreveal a specific neuronal circuitry that is involved in trust-

worthy behavior FIGURE 5. Oxytocin receptors are abun-dant in the amygdala; thus they can modulate its activity.

he higher the activity in the amygdala is, the higher anemotion of untrustworthiness is generated. Oxytocin actson its own receptors in the amygdala by reducing neuraactivity, thereby restoring an emotion of trustworthiness.

2. Admiration for virtue and for skills engages twoseparate neural systems

Admiration differs from trust, yet these two emotional ele-ments are related to each other: if one admires a person, heis likely to trust him. Admiration may represent a very im-

Amy

Untrustworthiness

Oxytocin

Amy

Oxtr Oxtr

+ +

FI RE . ne of the key elements during the doctor-patient

relationship is represented by the patients trust. The amygdala

Amy is responsible or untrustworthiness: the higher the amygdalaactivity, the more untrustworthy the judgments about a person.

Oxytocin increases trust by binding to its own receptors (Oxtr) on the

amyg a a an y n t n g ts act v ty.




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portant aspect o t e t erapist-patient encounter, or it cane e icite eit er y o serving virtuous e avior towar s

t e su ering o ot ers or y isp ays o virtuosic s i . In t efirst case, admiration has to do with social/psychologicacircumstances, i.e., virtue, whereas in the second case it isrelated to physical circumstances, i.e., skillful abilities(173).

As for compassion, admiration was found to engage theposteromedial cortices, i.e., the posterior cingulate cortex,the retrosplenial area, and the precuneus. However,whereas admiration for virtue induced activation in the in-ferior/posterior portion of the posteromedial cortices, ad-miration for skills produced a larger activation in the supe-rior/anterior portion of the posteromedial cortices (173)FIGURE 4.

3. Hope and hopelessness may be related to

serotonergic and noradrenergic mechanisms

Hope can be defined as a positive motivational state that isbased on a sense of successful goal-directed energy andplanning to meet goals (301, 302). A key element of hope,although not the only one, seems to be the current unsatis-factory conditions of life, which may involve deprivation,damage, or threat (205). Motivation is central to hope, andactually it interacts with goal-directed behavior. High-hopeindividuals are capable of using alternative pathways if animpediment of any sort occurs in the planned behavior sothat the same goal can be reached in a different way (301).

Some stu ies in icate t at ope as ene cia e ects onhealth, for example, better coping with arthritis (301), burninjuries (28), fibromyalgia (10, 313), and pain (75, 300,301). In contrast, hopelessness and pessimism have beenfound to be associated with illness and mortality (120, 255,284, 306). However, since hopelessness is often associatewith depression, some negative effects can sometimes beattributed to the depressive symptoms and not to hopeless-ness itself.

It is not easy to approach hope and hopelessness from aneurophysiological perspective. For example, hopelessness

and helplessness are often considered together. However,whereas hopelessness can be considered as a negative ex-pectation with respect to the future, helplessness can beviewed as unrealistically low concepts of the own capabili-ties (e.g., see Re . 165). In 1967 it was reporte t at ogsundergoing electric shocks not contingent on their behaviorshowed a subsequent difficulty to escape and avoid theshocks (251). This occurred because the dogs learned thatthe shocks were independent of any responses. This phe-nomenon, w ic was ca e earne e p essness, asbeen used as an animal model of depression, despite a re-formulation in more cognitive terms by Abramson et al. (1,2), in which hopelessness was considered as a subset of

helplessness.

Serotonin as een oun to e invo ve in earne e p ess-ness. For examp e, in some stu ies, a ter t e presentation ouncontro a e s oc s, rats cou e separate into twodifferent groups. Whereas one group did not learn to escapea controllable shock after previous exposure to uncontrol-able shocks (learned helpless rats), another group learned

an a equate response (non earne e p ess rats). T eearne e p ess rats s owe an upregu ation o serotonin

receptors in some regions of the brain, such as the cortex,hippocampus, septum, and hypothalamus, whereas a down-regulation was observed in the hypothalamus. Changes in pre-synapticactivity at serotonergicsynapses caused by uncontrol-lable shocks have also been described in the hippocampus andhypothalamus of learned helpless rats (20, 113, 114).

Interestingly, a negative correlation between prefrontalbinding to serotonin 5-HT Areceptors and levels of hope-lessness was found in attempted suicide, according to the

rule: the lower the binding to serotonin receptors, the higherthe degree of hopelessness (325). An activation of the hy-pothalamus-pituitary-adrenal axis has also been found in anumber of studies that used inescapable shocks as a model(165), and indeed, adverse experiences might lead to stresssensitivity. This, in turn, would lead to excessive norepi-nephrine release and its subsequent depletion, with the con-sequent hopelessness (228).

4. Attributing a positive meaning to pain coactivatespioid and cannabinoid systems

Empathic and compassionate behavior is not always in-

c u e in t e octors ac groun an armamentarium,an a communication is sometimes the rule in routinemedical practice. The doctors words and behavior mayinduce negative expectations in the patient and may lead toclinical worsening. One good example is represented by theway of communicating negative diagnoses, a task that re-quires good empathic and compassionate abilities. The im-pact of a negative diagnosis on the patients brain and bodycan be substantial and can induce real worsening, e.g., painincrease. Anxiety plays a key role in these situations, and abad interaction may indeed increase the patients negativeemotions. In this regard, the mechanisms underlying anxi-

ety- and nocebo-induced hyperalgesia have been investi-gated in some detail and will be described in section V A5.

In this regard, the different meaning that is attributed to asymptom suc as pain can e crucia in t e g o a experi-ence of pain. For example, clinicians have long known thatcancer pain can be perceived as more unpleasant than post-operative pain (94, 127, 299), and this can be due to thedifferent meanings of cancer on the one hand and of surgeryon t e ot er. W ereas t e ormer o ten means eat , t elatter is associated with healing and recovery. Likewise,different religions attribute different meanings to pain ansuffering, and this may lead to different pain experiences

(164, 194, 342).

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On y very recent y were i erent attri utions to pain inves-tigate wit a neuro io ogica approac , an t is approacmay ave pro oun imp ications in me ica practice, orexample, within the context of negative diagnoses. In fact,how patients interpret their own pain experience can makea big difference. Benedetti et al. (66) changed the meaningo pain rom negativeto positivein ea t y su jects t rougver a suggestions. T e su jects a to to erate isc emicarm pain as long as possible. However, whereas one groupwas informed about the aversive nature of the task, as donein any pain study, a second group was told that the ischemiawould be beneficial to the muscles, thus stressing the bene-ficial nature of the pain endurance task. In this latter group,pain tolerance was significantly higher compared with thefirst one, an effect that was partially blocked by the opioidantagonist naltrexone alone and by the cannabinoid antag-onist rimonabant alone. However, the increased tolerancewas antagonized completely by the combined administra-

tion of naltrexone and rimonabant, which suggests that apositive approach to pain reduces the global pain experi-ence through the coactivation of the opioid and cannabi-noid systems. These findings show that the way patientsinterpret their own symptoms may have a dramatic effecton their emotional experience.

IV. MECHANISM-BASED CLASSIFICATIONF PLA EB RE P N E

. Mechanism-Base or Disease-Base

Classification of Placebo Responses?

The final and perhaps the most important step in the doc-tor-patient interaction is represented by the very act of re-ceiving a treatment FIGURE 3. The ritual of the therapeuticact and the effects that it may have on the therapeutic out-come is the element that has received great attention in thepast few years. As described in section I, the psychosocialcontext and the therapeutic ritual surrounding the treat-ment and the patient FIGURE 1 have been approached byusing the placebo response as a model to understand theunderlying physiological mechanisms. The doctor, and

more in general the healer, is surely the key element in thistherapeutic ritual, as we have seen in sections II and III.

What we have learned over the past years is that there is nota sing e mec anism o t e p ace o response, an actua ythere is not a single placebo response but many, so that

ifferent mechanisms are involve in ifferent me ical con-ditions and therapeutic interventions. One of the mainproblems in current placebo research is how these differentmec anisms s ou e consi ere an c assi e . For exam-ple, placebo administration can induce either anxiety reduc-tion or activation of reward mechanisms, depending ondifferent circumstances. Likewise, different forms of learn-

ing can take part in placebo responsiveness in different con-

itions, ranging rom c assica con itioning to socia earn-ing. T ere ore, a rst approac to t e c assi cation o i -erent placebo responses might be based on the mechanismhat is involve .

On the other hand, today we do not know exactly when anin w ic con itions t ese mec anisms ta e p ace. For ex-ample, anxiety reduction might be important only in somemedical conditions but not in others. Or, otherwise, learn-ing might be a common mechanism across all medical con-ditions. Reasoning in this way, a second approach to the

lassification of different placebo responses, is a disease-based classification whereby the biological underpinningsare investigated in different conditions such as pain andParkinsons disease.

herefore, it is not clear whether we should differentiate theplacebo responses on the basis of the mechanism or rather

on the basis of the disease. This will be a future challenge inplacebo research, that is, to understand where (in whichdisease), when (in which circumstance), and how (withwhich mechanisms) placebos work. Therefore, due to ourimite un erstan ing o t e re ations ip etween mec a-

nisms and diseases, I will present both approaches. In thissection IV, the general mechanisms that have been identifiedare escri e FIGURE 6, whereas in section V the placeboresponses will described in different diseases.

B. Expectations of Therapeutic Benefit Playa Key Role in Many Conditions

Most of the studies aimed at identifying the underpinningsof the placebo effect have focused on expectations as themain mechanism, although today we do not know exactly iexpectations are important in all medical conditions. Ex-pectations of a future outcome are usually held by individ-uals about their own responses. Positive expectations leadto adopting a particular response, whereas negative expec-tations lead to its inhibition (187, 188). Expectations mayalso induce a decrease in self-defeating thoughts when ex-pecting a positive outcome (308), and other factors maycontribute such as motivation (269).

From both a psychological and a neuroscientific standpoint,expecting a future event may involve several brain mecha-nisms that aim to prepare the body to anticipate that event.For examp e, expecting a uture positive outcome may eato anxiety reduction and/or reward mechanisms activation,whereas expecting a negative outcome produces anticipa-tory anxiety, which is very important in anticipating a pos-sible threat. Indeed, both subjective anxiety (122, 231, 327)an anxiety-re ate rain activity (256) ave een oun to

e reduced after placebo administration.

Expectations may also induce changes through the activa-

tion of the reward circuit. These mechanisms are tradition-




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ally studied by using natural rewards, like food, as well asmonetary and drug rewards (176, 241). In the case of theplacebo response, the reward is the therapeutic benefit itselfan t e consequent c inica improvement, w ic representpowerful rewards for the suffering patient. The nucleus ac-cumbens plays a key role in reward mechanisms, and sev-eral studies found an increased activity of the nucleus ac-

cumbens and dopaminergic activity after placebo adminis-tration in Par insons isease (98, 99, 217), epression(229), and pain (287, 288). A detailed account will be givenin the sections on pain, Parkinsons disease, and depression.

C. The Placebo Response Involvesearn ng ec an sms

Patients can associate shape, color, and taste of a pill withsymptom amelioration, such as pain decrease. Several otherstimuli can be associated with clinical improvement, such assyringes, stethoscopes, white coats, hospitals, doctors,

nurses, and so on. The mechanism that underlies this effectis classical conditioning, whereby a neutral stimulus, e.g.,the color and shape of a pill, can become effective if repeat-edly associated with an unconditioned stimulus, i.e., the

rug insi e t e pi . Many p ace o responses can e attri -uted to this associative learning, whereby the placebo is theneutral stimulus itself. In one of the first stu ies on thebiology of the placebo effect (169), motor changes wereobserved in the rat after an injection of scopolamine, andt e same c anges occurre i an injection o sa ine so ution(placebo) was performed after the injection of scopolamine.

In clinical practice, these sequence effects are common (16,

22, 33, 34, 204, 312), and they can also be exploited in

clinical practice (106). Learning effects can be reproducedin t e experimenta setting as we . For examp e, Vou ouriset al. (331, 332) associated a nonanesthetic cream (placebo)with the surreptitious reduction of the intensity of painfulstimulation, so as to make the subjects believe that thecream was an effective anesthetic. These subjects, who hadexperienced a true anesthesia/analgesia, became strong

placebo responders, which suggests that conditioning is im-portant. However, expectation was found to be crucial,because no placebo analgesic effect was found if the subjectswere told that the cream was inert (243). This suggests that,during a conditioning procedure, conscious expectations ofa future outcome play a major role.

Expectation and conditioning are not necessarily mutuallyexclusive, as they may represent two sides of the same coin(308). In other words, a conditioning procedure might leadto placebo responses through a mechanism of reinforceexpectations. Indeed, in the 1960s, a different interpreta-tion of classical conditioning was put forward. According tothis reinterpretation, conditioning does not depend merelyon the pairing of conditioned and unconditioned stimuli, buton the cognitive information of the conditioned stimulus(276). Therefore, a conditioning procedure would lead to theexpectation that a given event will follow another event (189,

75, 276).

Despite the reinterpretation of conditioning in cognitiveterms, con itione p ace o responses in umans are notalways cognitively mediated. For example, it has been sug-

ested that unconscious conditioning is important in thoseplacebo responses that involve unconscious physiological

functions, whereas it is cognitively mediated when con-

Sociallearning

Placebo(sham treatment)

Expectationof reward

Learning-reinforced

expectations

Pavlovianconditioning

Personalitytraits

Clinical Improvement

Expectation-modulated

anxietyGenetics

FI RE . This figure includes only the psychobiological factors o FI RE 2. It can e seen that severalpsychological and biological factors may be involved in the clinical improvement following administration of aplacebo. Therefore, there is not a single placebo response but many, with different mechanisms across

different medical conditions and therapeutic interventions.

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scious processes come into p ay (65). T ere ore, many p a-ce o e ects can e exp aine in t e context o con itioningt eories (3, 252, 295). In act, a p ace o is y e nition aneutral stimulus with no therapeutic effects, in the sameway as a conditioned stimulus is by definition neutral. Like-wise, a placebo response is by definition elicited by a neutrastimu us, in t e same way as a con itione response is in-

uce y a neutra stimu us.

Conditioning is not the only learning mechanism that maybe involved in placebo phenomena. Social learning is an-other form of learning whereby people learn from one an-other by observation and imitation. As it will described inthe section on pain, placebo effects can be elicited by sociallearning through the observation of others who respond toa painkiller (91).

D. Some Placebo Responses May Be Relatedto ersona ty ra ts

A central issue in placebo research is whether individualspossess one or more specific characteristics, which can reli-ably identify them a priori as placebo responders or pla-cebo nonresponders, with important implications for botclinical trials design and personalized therapy optimization.Some studies have found that individual differences in sug-gesti i ity may contri ute to t e magnitu e o p ace o an-algesia. In fact, the largest placebo responses were found inhighly suggestible subjects who received suggestions pre-sumed to elicit high expectations for drug efficacy (100).

Pessimists have been found to be more prone than optimiststo o ow a negative p ace o (noce o) expectation, w icsuggests that the personality variable optimism-pessimismrelates to placebo responding (139). In addition, individualswere tested on the basis of their level of optimism, and itwas found that optimism was positively associated withbetter sleep quality after administration of a placebo sleep-ing treatment, thus suggesting that different degrees of op-timism relate to placebo responding (140).

E. Different Genetic Variants Affectlacebo Responding

Recently, substantial placebo responses have been foundfor some genetic variants, for example in some psychiatric

isor ers (137, 274). In one stu y (137), patients wit so-cial anxiety disorder were genotyped with respect tothe serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the trypto-phan hydroxylase-2 (TPH2) gene promoter. With the use ofunctional neuroimaging, it was found that only those pa-tients who were homozygous for the long allele of the5-HTTLPR or the G variant of the TPH2 G-703T polymor-phism showed robust placebo responses and reduced activ-ity in the amygdala. Conversely, carriers of short or T alleles

did not show placebo responses.

In anot er stu y in patients wit major epressive isor er(209), po ymorp isms in genes enco ing t e cata o ic en-zymes catechol- -methyltransferase (COMT) and mono-amine oxidase A were examined. Small placebo responseswere found in those patients with monoamine oxidase AG/T polymorphisms (rs6323) coding for the highest activityorm o t e enzyme (G or G/G). Simi ar y, ower p ace o

responses were found in those patients with ValMet cat-echol-O-methyltransferase polymorphisms coding for alower-activity form of the enzyme (2 Met alleles).

In a more recent study, the COMT functional val158metpolymorphism was found to be associated with the placeboeffect in irritable bowel syndrome. The strongest placeboresponse occurred in Met/Met homozygotes (154). There-fore, the role of genetic factors in placebo responding ap-pears to be an important factor across a number of diseases,ranging from neuropsychiatric to gastrointestinal/psycho-

somatic isor ers.

F. Other Possible Explanations HaveBeen Proposed

In addition to the classical psychological, neuroscientific,and biomedical approach, other perspectives of the placebophenomenon have been proposed. For example, medicalanthropologists have put forward the concept of embodi-ment. According to this view, our experiences are not onlystored as conscious memories, but they are imprinted di-rectly onto our body representation as well, with no con-scious processes involved. Accordingly, placebo and no-cebo effects would represent positive and negative effects oembodiment, respectively. This process does not need theinvolvement of conscious expectations (317). A body rep-resentation c ange can e ac ieve just y t e comp exityo t e ritua o t e t erapeutic act. Crucia in t e t erapeuticritual is the doctor-patient relationship, with empathy, at-titudes, behaviors, as well as gesture and recitation all con-tributing to the positive treatment outcome (317).

V. DI EA E-BA ED LA IFI ATI

F PLA EB RE P N E

Differently from the previous section, the disease-basec assi cation approac es t e p ace o e ect y ana yzing asingle medical condition, such as pain and Parkinsons dis-ease. Indeed, most of our knowledge on the physiologicalmechanisms of the placebo response comes from this ap-proach. In many studies, however, placebos were adminis-tered without specifically investigating anxiety modulationor reward mechanisms or learning. Therefore, today we donot know exactly whether or not all these mechanisms takepart in placebo responsiveness in a single condition such aspain. Despite these limitations, the disease-based approach

has been the most productive in the past few years. One of




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t e most important uture c a enges o p ace o researcwi e to un erstan in w ic me ica con itions a t emec anisms iste in section IV an FI URE are present.Today the most studied and understood conditions are cer-tainly represented by pain, Parkinsons disease, and the im-mune and hormonal responses.

. ace o na ges a s t e ostStudied and Understood Type of

lacebo Response

1. Expectation is the most important factor inplacebo analgesia

The reason why pain is the most studied condition is two-fold. First, pain is a subjective experience that undergoespsychological and social modulation more than any othercon ition. T e ne tuning o pain y many psyc osocia

actors ma es pain an exce ent mo e or investigating t eplacebo response. Second, modern placebo research hasbeen influenced by the work by Beecher in the 1950s (36)who, as an army doctor during the Second World War,faced the problem of the lack of strong analgesics on thebattlefield. Therefore, he treated his soldier patients withplacebos many times and found that many subjects re-sponded quite well very often. Despite several methodolog-ical flaws (44), Beechers merit was to boost the interest oft e scienti c community in t e p ace o e ect.

Today it is not clear why some individuals respond to pla-cebos whereas some other individuals do not (see section

). It should be noted that a mean change in a placebogroup might be seen in different situations, e.g., if all sub-jects in t e p ace o group s ow a mo erate response or,otherwise, a small subset of subjects show a large responseand others show no response at all. These variations areresponsible for the large variability in placebo responsesthat is observed following placebo administration. For ex-ample, Levine et al. (211) found a percentage of 39%, Bene-detti (40) of 26.9%, and Petrovic et al. (257) of 56%.

Expectation seems to play a key role in placebo analgesia(188, 243, 269, 270). For example, Benedetti et al. (65)

performed a pharmacological preconditioning for 2 days ina row with ketorolac, a nonopioid analgesic. On the thirdday, ketorolac was replaced with a placebo along with ver-bal suggestions of analgesia, and a powerful placebo anal-gesic response was observed. In a second group, the sameproce ure wit etoro ac was carrie out to see w et ert is p ace o response was ue to t e p armaco ogica pre-conditioning itself. However, on the third day, the placebowas given along with verbal suggestions that the drug was ahyperalgesic agent. Not only were these instructions suffi-cient to block placebo analgesia completely, but they alsopro uce ypera gesia. T is n ing in icates t at p ace oanalgesia depended on expectation of pain decrease, even

though a preconditioning procedure was performed.

e ecrease e ectiveness o i en treatments representsone o t e est evi ences o t e crucia ro e o expectation.In this case, a painkiller is given covertly (unexpectedly)un e nownst to t e patient, an t e outcome o owing t ehidden (unexpected) administration is compared with thatfollowing an open (expected) administration. In postoper-ative pain following the extraction of the third molar (210,

13), it was found that a hidden injection of a 68 mgintravenous dose of morphine corresponds to an open in-jection of saline solution in full view of the patient (pla-cebo). Thus a placebo is as powerful as 68 mg of mor-phine. This means that an open injection of morphine ismore effective than a hidden injection because in the hiddenadministration condition there is no placebo component. Asystematic study of the differences between open (expected)and hidden (unexpected) administrations of drugs has beenperformed for five widely used painkillers (morphine, bu-prenorphine, tramadol, ketorolac, metamizol) in the post-

operative setting (19, 57, 62, 92). It was found that theana gesic ose nee e to re uce t e pain y 50% (ADwas much higher with hidden infusions than with open onesor all five painkillers, indicating that a hidden administra-ion is less effective than an open one. In addition, it wasound that pain ratings were much higher with a hidden

injection than with an open one.

2. Both endogenous opioids and endocannabinoidsmay take part in placebo analgesia

he placebo effect represents today one of the most inter-esting models to understand the endogenous mechanisms of

ana gesia (42), an in ee , p ace os ave een oun toactivate different endogenous antinociceptive systems. The

rst study that was aimed at understanding the biologicamechanisms of placebo analgesia used naloxone as an an-agonist of the opioid receptors in patients with postopera-ive pain who had undergone the extraction of the third

molar (212). The investigators found a disruption of pla-ebo analgesia after naloxone administration, which indi-ates the involvement of endogenous opioids in the placebo

analgesic effect. The involvement of the endogenous opioidnetwork in the analgesic placebo response was then con-firmed by a number of studies (148, 210, 220).

In a long series of experiments with rigorous experimentalesign, which were performed between 1995 and 1999,

many mechanisms were clarified and the role o endogenousopioi s in p ace o ana gesia was etter exp aine FIGURE 7With the use of experimental ischemic arm pain, it was

efinitely clarified that the effect following naloxone ad-ministration could be attributed to the blockade of placebo-induced opioid activation (40). In addition, the effects of a

holecystokinin (CCK) antagonist, proglumide, on placeboanalgesia was tested on the basis of the anti-opioid action oCCK. It was found that proglumide potentiated placeboanalgesia, which represents a novel and indirect way to test

he opioid hypothesis (40, 51). More recent research has

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shown that the activation of the CCK receptors by means ofthe agonist pentagastrin is capable of blocking the pla-cebo analgesic response, thus emphasizing the role ofCCK as an anti-opioid agent that may interfere withplacebo responses (53).

On the basis that the placebo analgesic effect is not alwaysmediated by endogenous opioids (147), Fields and Levine(128) suggested that different physical, psychological, an

environmenta situations cou a ect t e en ogenous opi-oid systems differently. In fact, Amanzio and Benedetti (16)showed that placebo analgesia is mediated by both expec-tation and conditioning, but whereas the former activatesthe opioid systems, the latter activates nonopioid systems.Indeed, the opioid antagonist naloxone can block thoseplacebo responses that are induced by means of strong ex-pectation cues. Similarly, if a placebo is given after repeatedadministrations of morphine (preconditioning procedure),the placebo response can be blocked by naloxone. Con-versely, if the placebo response is induced by means of priorconditioning with a nonopioid drug, such as nonsteroid

anti-inflammatory drugs (NSAIDs), it is naloxone insensi-tive (16).

On the basis of these findings, Benedetti and collaborators(52) in uce opioi or nonopioi p ace o ana gesic re-sponses and assessed the effects of the CB1 cannabinoidreceptor antagonist rimonabant. Differently from nalox-one, rimonabant had no effect on opioid-induced placeboanalgesia following morphine preconditioning, whereas itcomp ete y oc e p ace o ana gesia o owing nonopioipreconditioning with the NSAID ketorolac. These findingsindicate that those placebo analgesic responses that are elic-ited by NSAIDs conditioning are mediated by CB1 canna-

binoid receptors FIGURE 7.

Since the involvement of the CB1 cannabinoid receptors inplacebo analgesia is a very recent finding, little is knownabout their localization and activation. We only knowthat they are activated following a previous exposure toNSAIDs, which suggests that these drugs, besides the inhi-

ition of cyclooxygenase and prostaglandin synthesis, acti-vate an endocannabinoid pathway (52). In contrast, weknow more etails a out the activation an localization othe placebo-activated opioid systems. For example, specific

p ace o ana gesic responses can e o taine in i erentparts of the body (242, 270), and these responses are nal-oxone-reversible (55). If four noxious stimuli are applied tothe hands and feet and a placebo cream is applied to onehand only, pain is reduced only on the hand where thep ace o cream a een app ie . T is ig y speci c e ectis blocked by naloxone, suggesting that the placebo-acti-vated endogenous opioid systems have a precise and soma-totopic organization (55).

In 2002, Petrovic et al. (257) found that both a placebo andthe opioid agonist remifentanil affect the very same brain

regions in the cerebral cortex and in the brain stem, whichsuggests that placebo-induced and opioid-induced analge-sia share a common mechanism. A placebo induced theactivation o t e rostra anterior cingu ate cortex an t eorbitofrontal cortex, and there was a significant covariationin activity between the rostral anterior cingulate cortex andthe lower pons/medulla, and a subsignificant covariation

etween the rostral anterior cingulate cortex and the peri-aqueductal gray, which suggests that the descending rostraanterior cingulate/periaqueductal gray/rostral ventrome-dial medulla pain-modulating circuit is involved in placeboanalgesia. In 2005, Zubieta et al. (355) provided the firstdirect evidence of opioid-mediated placebo analgesia. With

the use of in vivo receptor binding techniques with the ra-

Proglumide

Naloxone Rimonabant

opioid receptors CB1 cannabinoid receptors

+ +

Previousexposure to

opioids

Previousexposure to

NSAIDs

CCK

Placebo

FI RE 7. he mechanism of the placebo analgesic response

Documents

Fabrizio Benedetti. Placebo and the New Physiology of the Doctor-patient Relationship