The Silent Healer the Role of Communication in Placebo Effects Jozien Bensing William Verheul 2009 Bensing Ask for permission before adopting

Placebo “ I will please” 2009 Bensing Ask for permission before adopting

Structure of Presentation A Bit of History Current Knowledge Looking Forward 2009 Bensing Ask for permission before adopting

A Bit of History

Current Knowledge

Looking Forward

Hooper’s Medical Dictionary (1811) Placebo: an epithet given to any medicine adapted more to please than to benefit the patient 2009 Bensing Ask for permission before adopting

Placebo: an epithet given to any medicine adapted more to please than to benefit the patient

Hippocrates, 460 – 400 B.C. “ some patients, though conscious that their condition is perilous, recover their health simply through their contentment with the goodness of the physician” precepts VI 2009 Bensing Ask for permission before adopting

“ some patients, though conscious that their condition is perilous, recover their health simply through their contentment with the goodness of the physician”

Around the midst of the 17th century, the times they were a’ changing …….. Throughout history, physicians have always been well aware of the healing power of a comforting attitude Acknowledgment: Hanneke de Haes 2009 Bensing Ask for permission before adopting Jan Steen, 1650 W. Chandler, 1785

Cartesian dualism Mind-body dichotomy Body is a machine Reductionistic approach René Descartes 1596 - 1650 Strategic Decision! Mind: domain of church Body: domain of physicians 2009 Bensing Ask for permission before adopting

Cartesian dualism

Mind-body dichotomy

Body is a machine

Reductionistic approach

This could be a happy marriage Unfortunately, there is a hierarchy 2009 Bensing Ask for permission before adopting The Science of Medicine The Art of Medicine

"Three-quarters of badly wounded men, although they have received no morphine for hours... have so little pain that they do not want pain relief medication, even though the questions raised remind them that such is available for the asking.” Pain in Men Wounded in Battle (1946) Henry Knowles Beecher 1904 - 1976 2009 Bensing Ask for permission before adopting

"Three-quarters of badly wounded men, although they have received no morphine for hours... have so little pain that they do not want pain relief medication, even though the questions raised remind them that such is available for the asking.”

Pain in Men Wounded in Battle (1946)

1955 In the JAMA, Beecher announces – based on a review of 15 clinical studies - that on average 35 percent of a drug’s or a doctor’s succes is due to the patient’s expectation of a desired outcome, or the “placebo effect”: “ The powerful Placebo” Henry Knowles Beecher 2009 Bensing Ask for permission before adopting

1955

In the JAMA, Beecher announces – based on a review of 15 clinical studies - that on average 35 percent of a drug’s or a doctor’s succes is due to the patient’s expectation of a desired outcome, or the “placebo effect”:

“ The powerful Placebo”

Beecher Placebo research Placebo-controlled clinical trials ? 2009 Bensing Ask for permission before adopting

placebo-effects in RCT’s In biomedical research only the therapeutical effect is considered Hrobjartsson et al, 2002 2009 Bensing Ask for permission before adopting Therapeutical effect control placebo intervention

In biomedical research only the therapeutical effect is considered

In biomedical research placebo-effects are often considered as noise or as a nuisance However, these are a fascinating target for scientific inquiry Hrobjartsson et al, 2002 placebo-effects: noise or focus? 2009 Bensing Ask for permission before adopting control placebo intervention placebo effect

In biomedical research placebo-effects are often considered as noise or as a nuisance

However, these are a fascinating target for scientific inquiry

It is getting time to open the black box of the physician’s healing power White, 1988 How can we learn to understand (and thus enhance) placebo-effects? 2009 Bensing Ask for permission before adopting

Structure of Presentation A bit of history Current knowledge Looking forward 2009 Bensing Ask for permission before adopting

A bit of history

Current knowledge

Looking forward

How do patients recover? Dutch Medical Schools (p/y): 2000 clinical trials 900 PhD theses 7500 publications 2009 Bensing Ask for permission before adopting Natural course Biomedical treatment Placebo (context) effects Health outcome

Placebo: a relic from the past? WIRED MAGAZINE: 17.09.2009 Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why. Steve Silberman 2009 Bensing Ask for permission before adopting

WIRED MAGAZINE: 17.09.2009

Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why.

Steve Silberman

What do we mean with ‘placebo effects’? Placebo effects are the aspecific or nonspecific effects of a medical treatment on patients’ health or wellbeing (Shapiro & Shapiro, 1997) Placebo effects are the incidental factors of a treatment to be discerned from the characteristic factors of a treatment ( Grünbaum, 1986; Hrobjartsson, 2002) Placebo effects are the genuine psychological or physiological effects, which are attributable to receiving a substance or undergoing a procedure, but are not due to the inherent powers of that substance or procedure (Stewart-Williams et al. 2004) 2009 Bensing Ask for permission before adopting

Placebo effects are the aspecific or nonspecific effects of a medical treatment on patients’ health or wellbeing (Shapiro & Shapiro, 1997)

Placebo effects are the incidental factors of a treatment to be discerned from the characteristic factors of a treatment ( Grünbaum, 1986; Hrobjartsson, 2002)

Placebo effects are the genuine psychological or physiological effects, which are attributable to receiving a substance or undergoing a procedure, but are not due to the inherent powers of that substance or procedure (Stewart-Williams et al. 2004)

The content of the placebo-concept is temporary If we understand the mechanisms: it is no longer non-specific or a-specific we learn to understand how it exactly works It is no longer incidental we can apply it in a planned and systematic way We can make it an integrated part of medical treatment and teaching medicine 2009 Bensing Ask for permission before adopting

If we understand the mechanisms:

it is no longer non-specific or a-specific we learn to understand how it exactly works

It is no longer incidental we can apply it in a planned and systematic way

We can make it an integrated part of medical treatment and teaching medicine

Non-specific or incidental factors can also have negative influences on patient outcomes Nocebo effects 2009 Bensing Ask for permission before adopting

Are placebo effects real and robust? NO Hrobjartsson , Nw Eng J Med , 2002 Hrobjartsson , J Int Med , 2004 Hrobjartsson , J Clin Epid , 2006 YES DiBlasi , Lancet , 2001 Vase , Pain , 2002 Guess , BMJ-books , 2002 Sauro , J Psychosom Res , 2003 Hyland, Clinical Medicine , 2003 Wager , Science , 2004 Stewart-Williams , Psych Bull , 2004 Collaca , Nature , 2005 Wampold , J Clin Psy, 2007 Price , Ann Psych Rev , 2008 Placebo-effects are always demonstrated in those studies where placebo-effects can be expected to exist 2009 Bensing Ask for permission before adopting

NO

Hrobjartsson , Nw Eng J Med , 2002

Hrobjartsson , J Int Med , 2004

Hrobjartsson , J Clin Epid , 2006

YES

DiBlasi , Lancet , 2001

Vase , Pain , 2002

Guess , BMJ-books , 2002

Sauro , J Psychosom Res , 2003

Hyland, Clinical Medicine , 2003

Wager , Science , 2004

Stewart-Williams , Psych Bull , 2004

Collaca , Nature , 2005

Wampold , J Clin Psy, 2007

Price , Ann Psych Rev , 2008

Where do we find placebo-effects? Asthma Bronchitis Common cold Coughing Heart failure Hypertension Herpes simplex Parkinson Rheumatoïd arthritis etcetera Anxiety Depression Schizofrenia Psychoneuroses Stress disorders Psychosomatic disorders Medically Unexplained Symptoms Pain 2009 Bensing Ask for permission before adopting

Asthma

Bronchitis

Common cold

Coughing

Heart failure

Hypertension

Herpes simplex

Parkinson

Rheumatoïd arthritis

etcetera

Anxiety

Depression

Schizofrenia

Psychoneuroses

Stress disorders

Psychosomatic disorders

Medically Unexplained Symptoms

Pain

What can cause placebo effects? Treatment characteristics (e.g. colour, size, shape of drug) Health care setting (e.g. home, hospital, room layout) Patient characteristics (e.g. illness / treatment beliefs, anxiety, adherence) Patient-practitioner relationship (e.g. compassion, reassurance, suggestion) Practitioners characteristics (e.g. status, sex, illness and treatment beliefs) DiBlasi et al, Lancet, 2001 2009 Bensing Ask for permission before adopting

Mechanisms behind placebo effects Classic Conditioning Positive or Negative Expectancies Positive or Negative Affect These mechanisms are interlinked in many ways Van Dulmen & Bensing, 2001 2009 Bensing Ask for permission before adopting

Classic Conditioning

Positive or Negative Expectancies

Positive or Negative Affect

Mechanism 1: conditioning A therapy or therapeutic procedure can produce a context-effect on health outcome, when it is associated – consciously or unconsciously – with previous experiences These experiences (and thus the health outcmes) can be either positive or negative 2009 Bensing Ask for permission before adopting

A therapy or therapeutic procedure can produce a context-effect on health outcome, when it is associated – consciously or unconsciously – with previous experiences

These experiences (and thus the health outcmes) can be either positive or negative

Mechanism 1: classic conditioning The natural response of a dog on the infusion of adrenaline is: elevated blood pressure Amaral & Sabbatini, 1999 2009 Bensing Ask for permission before adopting

The natural response of a dog on the infusion of acethylcholine is: lowered blood pressure Mechanism 1: classic conditioning 2009 Bensing Ask for permission before adopting

Amaral & Sabbatini, 1999 Mechanism 1: classic conditioning 2009 Bensing Ask for permission before adopting

Review placebo effects based on conditioning Conditioned placebo-responses have been demonstrated in human beings and in animals The effects in humans include pain relief, immunosuppression (MS), the production of hormones (Parkinson) a.o. Conditioning seems to be ‘hardwired’ in the brain Conditioning can take place unconsciously and consciously CAVEAT! If consciously, it is related to expectancies Stewart-Wiliams, 2004, Price, 2008 2009 Bensing Ask for permission before adopting

Conditioned placebo-responses have been demonstrated in human beings and in animals

The effects in humans include pain relief, immunosuppression (MS), the production of hormones (Parkinson) a.o.

Conditioning seems to be ‘hardwired’ in the brain

Conditioning can take place unconsciously and consciously

CAVEAT! If consciously, it is related to expectancies

A medical treatment or procedure can produce a placebo-effect because the recipient expects it to. Expectancies may be seen as: the patients’ beliefs about the efficacy of treatment (outcome expectancies) and the patients’ beliefs about their abilities to cope with the disease and its treatment (self-efficacy). Mechanism 2: expectancies Crow, 1999, Stewart-Williams, 2004 2009 Bensing Ask for permission before adopting

A medical treatment or procedure can produce a placebo-effect because the recipient expects it to.

Expectancies may be seen as:

the patients’ beliefs about the efficacy of treatment (outcome expectancies) and

the patients’ beliefs about their abilities to cope with the disease and its treatment (self-efficacy).

Pain reduction based on expectancies: open versus hidden treatment With several types of painkillers, patients experience more pain relief if they know the painkiller is administrated Price, 2008 2009 Bensing Ask for permission before adopting

Hidden vs open paradigma Colloca & Benedetti, 2005 2009 Bensing Ask for permission before adopting

Review Open vs Hidden Treatment: When manipulated experimentally, open treatment is more effective than hidden treatment Expectations seem to play an important role in producing these context effects These effects can be influenced both by previous experiences and/or verbal suggestion Amanzio et al. 2001, Benedetti et al.2003, Colloca et al. 2004, Levine & Gordon 1984 2009 Bensing Ask for permission before adopting

When manipulated experimentally, open treatment is more effective than hidden treatment

Expectations seem to play an important role in producing these context effects

These effects can be influenced both by previous experiences and/or verbal suggestion

Amanzio et al. 2001, Benedetti et al.2003, Colloca et al. 2004, Levine & Gordon 1984

Review: placebo effects based on expectancies Many controlled studies show the influence of expectancies on health outcomes There is a clear neurobiological substrate, meaning that these effects are genuine, not only response bias CAVEAT! In most studies no distinction is being made between positive words (raising expectations) and positive affect (a warm and friendly doctor) 2009 Bensing Ask for permission before adopting

Many controlled studies show the influence of expectancies on health outcomes

There is a clear neurobiological substrate, meaning that these effects are genuine, not only response bias

CAVEAT! In most studies no distinction is being made between positive words (raising expectations) and positive affect (a warm and friendly doctor)

Mechanism 3: Affect A medical treatment or procedure can produce a placebo-effect if it is administered in a warm and empathic way. This may serve a number of functions: Stress reduction Anxiety reduction Social support Its influence on health outcome is sometimes direct (relaxation), but also via moderators like self disclosure, self care, adherence, etc. DiBlasi, 2001, Kelley,1997, Epstein, 2007, Price, 2008, Street, 2009 2009 Bensing Ask for permission before adopting

A medical treatment or procedure can produce a placebo-effect if it is administered in a warm and empathic way.

This may serve a number of functions:

Stress reduction

Anxiety reduction

Social support

Its influence on health outcome is sometimes direct (relaxation), but also via moderators like self disclosure, self care, adherence, etc.

support for the role of affect in placebo effects The placebo-response is stronger in stressed and/or anxious patients (Wasan, 2006) The placebo-response is stronger in clinical pain than in experimental pain (Price, 1997, 2008) ‘ desire for relief’ is an important factor apart from ‘expectancies’ (Harrington, 1997) The processing of negative emotions shares neural networks with pain responses (Eisenberger, 2004) 2009 Bensing Ask for permission before adopting

The placebo-response is stronger in stressed and/or anxious patients (Wasan, 2006)

The placebo-response is stronger in clinical pain than in experimental pain (Price, 1997, 2008)

‘ desire for relief’ is an important factor apart from ‘expectancies’ (Harrington, 1997)

The processing of negative emotions shares neural networks with pain responses (Eisenberger, 2004)

studies on the effects of affect Affective communication (warmth, empathy, nodding, eye contact) has shown to be related to several patient outcomes, including: satisfaction, adherence health outcomes (Hb1ac, blood pressure) Stewart, 1995, DiBlasi et al, 2001, Beck et al, 2002, Griffin, 2004, Rao, 2007 2009 Bensing Ask for permission before adopting

Affective communication (warmth, empathy, nodding, eye contact) has shown to be related to several patient outcomes, including:

satisfaction,

adherence

health outcomes (Hb1ac, blood pressure)

Limitations in communication research Much research is descriptive and correlational RCT’s are conducted, but communication is often used as a container concept Rigorous experiments testing specified communication elements are difficult to perform it is unethical to confront real patients in clinical situations with negative affect (cold, impersonal communication) Communication is per se interactive, thus difficult to standardize Researchers are reluctant to adopt a reductionistic approach 2009 Bensing Ask for permission before adopting

Much research is descriptive and correlational

RCT’s are conducted, but communication is often used as a container concept

Rigorous experiments testing specified communication elements are difficult to perform

it is unethical to confront real patients in clinical situations with negative affect (cold, impersonal communication)

Communication is per se interactive, thus difficult to standardize

Researchers are reluctant to adopt a reductionistic approach

Placebo-effects exist and are genuine At least 3 mechanisms are responsible: Conditioning Expectancies Affect Communication seems to play an important role But can we really prove how? What do we know about placebo-effects? 2009 Bensing Ask for permission before adopting control placebo intervention placebo effect

Placebo-effects exist and are genuine

At least 3 mechanisms are responsible:

Conditioning

Expectancies

Affect

Communication seems to play an important role

But can we really prove how?

Structure of Presentation A Bit of History Current Knowledge Looking Forward (back to the future) 2009 Bensing Ask for permission before adopting

A Bit of History

Current Knowledge

Looking Forward (back to the future)

Medicine is a delicate balance between art, science and communication (Carole Guzman) 2009 Bensing Ask for permission before adopting

This could be a happy marriage Unfortunately, there is a hierarchy Art and science should be integrated 2009 Bensing Ask for permission before adopting The Science of Medicine The Art of Medicine

Neurocognitive sciences can help By providing knowledge about mind-body interaction By introducing new technologies By inspiring new methodologies 2009 Bensing Ask for permission before adopting

By providing knowledge about mind-body interaction

By introducing new technologies

By inspiring new methodologies

New knowledge: Neurobiological substrates of placebo effects Endogenuous opioids are found in placebo-responders ( Benedetti, 1999) Placebo-induced release of endogenous opioids has been obtained by using in vivo receptor binding with positron emission tomography ( Zubieta, 2005) Similar regions in the cerebral cortex and in the brainstem are affected by both a placebo and a painkiller (remifentanil) ( Petrovic, 2002) ; 2009 Bensing Ask for permission before adopting

Endogenuous opioids are found in placebo-responders ( Benedetti, 1999)

Placebo-induced release of endogenous opioids has been obtained by using in vivo receptor binding with positron emission tomography ( Zubieta, 2005)

Similar regions in the cerebral cortex and in the brainstem are affected by both a placebo and a painkiller (remifentanil) ( Petrovic, 2002)

New technologies (neuro-imaging) Collaca & Benedetti, 2005 2009 Bensing Ask for permission before adopting

New methodologies Analogue patient paradigm Standardized medical visits are watched by analogue patients The assumption is that watching a videotaped consultation produces the same effects as participating in this consultation Fogarty, 1999, Schmid Mast, 2005, 2007, 2008, Eide, 2008 2009 Bensing Ask for permission before adopting

Analogue patient paradigm

Standardized medical visits are watched by analogue patients

The assumption is that watching a videotaped consultation produces the same effects as participating in this consultation

Coherence of skin conductance ( participating in versus watching a medical visit) 2009 Bensing Ask for permission before adopting

New methodologies The human mirror system acts as the neurological hardware for analogue patients’ empathy for the patient This methodology has shown to be able to evoke discriminating reactions in response to different communication-stimuli Which opens the possibility of testing the effects of different communication elements on patient outcomes Fogarty, 1999, Schmid Mast, 2005, 2007, 2008 2009 Bensing Ask for permission before adopting

The human mirror system acts as the neurological hardware for analogue patients’ empathy for the patient

This methodology has shown to be able to evoke discriminating reactions in response to different communication-stimuli

Which opens the possibility of testing the effects of different communication elements on patient outcomes

Experimental conditions (2x2) Positive Affect Friendly and inviting welcome Showing empathy Eye contact & body posture Negative Affect Formal and cold welcome No empathic statements Little eye contact and diverted body posture Positive Expectancies Positive about the type of drugs Positive about expected effect on pain Negative Expectancies Drug is mentioned in a neutral way Hesitation about expected effect 2009 Bensing Ask for permission before adopting

Positive Affect

Friendly and inviting welcome

Showing empathy

Eye contact & body posture

Negative Affect

Formal and cold welcome

No empathic statements

Little eye contact and diverted body posture

Positive Expectancies

Positive about the type of drugs

Positive about expected effect on pain

Negative Expectancies

Drug is mentioned in a neutral way

Hesitation about expected effect

change in: "The treatment will help against the pain" Participating in visit Watching visit 2009 Bensing Ask for permission before adopting

change in "the pain will continue for a long time" Participating in visit Watching visit 2009 Bensing Ask for permission before adopting

Change in state anxiety Participating in visit Watching visit 2009 Bensing Ask for permission before adopting

Experiences with methodology Intervention check: positive Doctors & patients judged the videos as realistic The women had no problems ‘playing their role’ of a patient with severe period pain Most women had no problems with identifying themselves with the patient on video 2009 Bensing Ask for permission before adopting

Intervention check: positive

Doctors & patients judged the videos as realistic

The women had no problems ‘playing their role’ of a patient with severe period pain

Most women had no problems with identifying themselves with the patient on video

Reflection on results Raising expectations in itself is not sufficient to produce robust effects on patient outcomes Showing positive affect in itself is not sufficient to produce robust effects on patient oucomes It is the combination that works! Nocebo effects are evident as well 2009 Bensing Ask for permission before adopting

Raising expectations in itself is not sufficient to produce robust effects on patient outcomes

Showing positive affect in itself is not sufficient to produce robust effects on patient oucomes

It is the combination that works!

Nocebo effects are evident as well

General conclusions Placebo effects exist and are genuine, no response bias Three mechanisms (conditioning, expectancies and showing affect) seem to be responsible All three mechanisms have shown a neurobiological substrate, which takes placebo research out of the hazy area Placebo effects are often interlinked but can be manipulated in experimental designs Communication plays a major role 2009 Bensing Ask for permission before adopting

Placebo effects exist and are genuine, no response bias

Three mechanisms (conditioning, expectancies and showing affect) seem to be responsible

All three mechanisms have shown a neurobiological substrate, which takes placebo research out of the hazy area

Placebo effects are often interlinked but can be manipulated in experimental designs

Communication plays a major role

General Conclusions II Much progress has been made in the study of placebo effects in health care Thanks to: Multi- and Interdisciplinary efforts New technologies New methodologies Rigorous experimental testing But many new questions arise, eg. About the specific role of different communication elements An exciting research domain is developing really fast 2009 Bensing Ask for permission before adopting

Much progress has been made in the study of placebo effects in health care

Thanks to:

Multi- and Interdisciplinary efforts

New technologies

New methodologies

Rigorous experimental testing

But many new questions arise, eg. About the specific role of different communication elements

An exciting research domain is developing really fast

Let us open the black box of the physician’s healing power ! facilitating Open – closed questions EMPATHY Summarizing Eye contact Nodding Tailoring I nterruptions Expectancies Explicit vs implicit Information Being Positive - Neutral Experiences 2009 Bensing Ask for permission before adopting

For information: [email_address] [email_address] 2009 Bensing Ask for permission before adopting

2009 Bensing Ask for permission before adopting