Placebo in the past that placebos were subjective



Placebo is coined from the Latin “I
shall please”. It is considered a psychological phenomenon, where a patient
derives therapeutic (or negative in the case of Nocebo) effects from an inert, sham
or dummy treatment which acts as if it were an active drug or real treatment. However, understanding of the phenomena has moved on
since then with new
emerging technologies that can track, monitor and measure subcortical
neurophysiologic mechanisms in action whist taking placebo through specialised,
sensitive brain imaging equipment. This paper will detail some of these
technologies to allow for better understanding of the brain processes behind
therapeutic effects of placebo or the detrimental effects of nocebo. It will
look at some research into placebo, the
social environment that plays a role in placebo known as the ‘psychosocial’ environment and will
elaborate on the neurobiological
processes taking place in the brain through the patient’s conscious and unconscious brain in eliciting placebo
effects through prior conditioning,
reward expectations and anxiety modulation.


Brian imaging technologies

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!

order now

1Figure 1 – How Naloxone
counter the effects of opioid overdose in the body.

Figure 1 shows How naloxone is used to
counter the effects of opioid overdose. Opioids attach to receptors in the
brain, these opioids are made naturally in the body and are called endogenous
opioids. once they are attached they send signals to the brain which triggers
the ‘opioid effect’ which blocks pain.2 

Naloxone is a medication which is often
referred to as an ‘opioid antagonist as it is used to counter the effects of
opioid overdose and they only work in the body if opioids are present in the


was a misunderstanding in the past that placebos were subjective psychological
responses involving the cortical level of the brain only.   A 1978 study however challenged this notion. 3In this study of dental
postoperative pain showed that the pain could be blocked by naloxone, a
narcotic opioid antagonist drug; a drug that can temporarily remove opioids
from the receptors in the body to prevent the opioids from re-attaching to the
receptors for a limited time, which indicated that the placebo must have
actually caused an increase in endogenous opioids.  This showed that there was a placebo
analgesia and that the psychological mechanisms of both conditioning and expectation
had triggered the opioid system which was counteracted by the antagonist
naloxone. Although this was understood, now sensitive molecular imaging
technics can show this information in a visual form (Finniss
& Benedetti 2007, Amanzio & Benedetti 1999).


4Figure 2– Example of Functional imaging used to
demonstrate the original 1978 study.

5Functional imaging is a technique that allows for
detecting and measuring changes in: metabolism ,regional and chemical composition blood
flow and absorption



6Figure 3 – Neuroimaging   








It uses medical
image modalities, often through tracers or probes. Functional imaging has shown
that in the case of placebo analgesia that there is clear links to activation
and that this activation has increased functional correlation in the anterior
cingulate, prefrontal orbitofrontal and insular cortices, nucleus acumens,
amygdala, the brainstem periaqueductal grey matter and the spinal cord.  It allows for a visual mapping of brain
activity, providing information on the electrical and vascular interactions
determining the functional status of the brain. Functional imaging compromises
several techniques, ‘positron emission tomography (PET) which can reflect metabolic processes in the body, magnetencephalography (electroencephalography), which
allows for visualisation of neural responses and where they are located in the
brain, functional magnetic resonance imaging (fMRI) a non-invasive measurement
of brain activity through the measurement of oxygen in the blood.  This is possible because blood flow increases
in the areas of the brain in use, fMRI detects this activity using the
blood-oxygen-level dependent (BOLD) contrast. Another form of neuroimaging
utilised in placebo experiments is Quantitative
electroencephalography imaging – see figure 2. These technologies give a real
insight into the mechanisms in action during placebo.


Research in to Placebo


Kaptchuk, professor of medicine at Harvard Medical School, having carried out
many studies in Placebo, explains that it is not just imagination but the
schema of information already held within the brain as a result of past
experiences that comes to play, as an example, upon being advised of snakes in
the woods, an individual will perceive a long stick in the forest as a snake.
The brain uses the information through visual processing, utilising the
predictive mechanisms to instigate responses based on past experiences. He highlights
some key placebo research to underline, how misguided, he feels, the idea of a
placebo being merely the effects of taking an inert substance. 8His
team carried out an experiment which included three groups; one group had a
questionnaire but no treatment; the second had a placebo but no care engagement;
the third group had the placebo with the added paraphernalia of the healthcare
environment, warm interaction, attentive listening, thoughtful conversation and
tactile touching. 28% of patients in the no treatment group reported pain
relief; 44% of the placebo but no engagement reported pain relief; 60% of
patients in the full care engagement and placebo reported pain relief.



Figure 4 – Engaged Patient Results


graph below, shows the impact the caregiver and the environment has when
eliciting placebo effects, in the study (Kaptchuk BMJ 2008)


10Figure 5 – Psychosocial Context

This shows the process taking place in the brain from
the psychosocial context.

Placebo and the Social environment


11Fabrizio Benedetti, professor pf
physiology and neuroscience and a key resource of information on placebo,
further clarifies that the processes that are triggered in the brain are not as
a result of the placebo but rather what the placebo represents or symbolizes.  In a clinical setting, it is the
‘psychosocial context’, which sets in motion the neurobiological changes.





Figure 6 and 7 -12 Placebo – the
psychosocial context brain mechanisms                                         



13Figure 5 and 146:
The picture above shows how the environment forms a physical placebo – so a
Doctor’s surgery is actually giving a variety of stimuli to the patient with
its healing apparatus.  It activates the
patient’s senses like smell, touch and hearing. The Doctor’s empathy,
reassurance, physical presence, touch and body posture form the treatment the
patient is having. In a hospital, it is the clinical setting, the doctors and
nurses, the smell of the drugs, the machinery which symbolize to the patient a
place of healing.


Bernedetti explains the process:  Neurotransmitters are released and then binding
takes place to their corresponding receptors this in turn prompts the release
of further molecules in the brain or other organs among them hormones, immune
mediators and more neurotransmitters these set-in motion the physiological
changes than
are shown to
generate therapeutic effects.













15Table 1 –  Benedetti contends that the ‘placebo effect’ uses
different mechanisms in the brain. Outlined in the table below are the  

Type 1

Type 2

Type 2

Unconscious reactions

Conscious reactions

Conscious reactions

Classical (Also known as Pavlovian) conditioning

Expectation of reward

Anxiety modulation

Brain areas triggered: Dorsolateral prefrontal cortex

Brain areas triggered: Nucleus accubens – release of dopamine

Brain areas triggered: Orbitofrontal cortex among others.

For example – giving morphine every day to a
patient for 5 days and then giving an inert substitute on the 6th
day will generate a placebo effect, as the brain has been conditioned to
respond to the morphine by producing molecules that interact with the same
targets as the morphine.

Reward network of the brain – activated with the expectation of
food, sex, money etc.

The brains anxiety network
For example-  giving a
patient treatment and telling them their pain will go away, will allow for
their anxiety to decrease, triggering the release of neurotransmitters in the

side-view of the brain showing the regions involved in the conditioning
response, dorsolateral prefrontal cortex

side-view of the brain showing the reward regions involved in the brain,
nucleus accumbens

side-view of the brain showing the region of the brain involved orbitofrontal
cortex, during the placebo effect

When a pill is
administered, there is a completely unconscious association between two
stimuli: the pharmacologic effect and the psychosocial context, which may
include such things as the colour and shape of the pill. Unconscious
conditioning has been demonstrated in both animals and humans.

Conscious expectations are important for conscious
physiological functions like pain and motor performance

Conscious expectations are important for conscious
physiological functions like pain and motor performance


16Furthermore, a study of patients with
switched off pacemakers, showed the heart condition of the patients in the
placebo group improved as a result of being less anxious and producing lower
levels of catecholamine stress hormones which are known to alter heart function.
This reflects the many biochemical pathways and associated organs which are
involved in the anxiety and reward networks.

It appears the unconscious
conditioning has a greater capacity for physiological functions like activation
of immune mediators or hormone secretion for instance if a patient was given a
placebo and told it would increase growth hormone levels, it will have no effect,
according to Benedetti, however, giving a drug that actively raises hormone
levels for two days running and then replacing the drug with a placebo will
reflect a rise in hormone levels. 

Finally, an interesting experiment
Kaptchuk’s team undertook involving two groups, one group had no treatment and
the second group had a placebo that was clearly labelled placebo with full
transparency. 35% of the no treatment group reported pain improvement and 60 %
of the open placebo group reported pain improvement. This shows placebo has
effects even when patients know they are taking placebo, which points to the
importance of the psychosocial environment and the importance of Doctor patient




In summary, the
data available suggests that single neurobiological or psychobiological
mechanisms are unable to explain the phenomena of placebo and Nocebo, instead
placebo or nocebo responses are mediated across diseases and experimental
conditions for which common and system-specific mechanisms coexist. As a
result, Benedetti, implicates multiple
brain systems and neurochemical mediators which include opioids and dopamine
and in the case of nocebo, according to some studies, the opposite, cholecystokinine
(CCK) induces nocebo hyperalgesia transforming anxiety into pain. Functional imaging shows that in the case of placebo
analgesia a top-down process is taking place which is dependent on the frontal
cortical areas that both generate and maintain cognitive expectancies. The
psychosocial environment plays a part in eliciting placebo or nocebo effects,
as Ted Kaptchuk’s transparent study of placebo shows. Depending on the nature
of the problem different processes are at work in the brain. Anxiety
modulation, brain reward functions, Classical (Pavlovian) conditioning and
social learning.




1 Understanding
Naloxone – Harm Reduction Coalition.
(accessed 14 Dec 2017).

2 How do opioids work in the
brain?. 2017. (accessed 7
Dec 2017).


3 Lancet.  The mechanism of placebo

Levine JD, Gordon NC, Fields HL – 
Published 1978 Sep 23;2(8091):654-7 accessed 20/11/2017


4 Lancet.  The mechanism of placebo analgesia.

Levine JD, Gordon NC, Fields HL –  Published 1978 Sep 23;2(8091):654-7 accessed
– imaging – P.M. Smith-Jones, in Comprehensive Medicinal
Chemistry 11, 2007 accessed 20/11/2017 &  Nina Shevzov – Zebrun& Andrei I.
Hollodny, in Image Guided Neurosurgery, 2015 accessed 20/11/207

6 Colloca L, Benedetti F (2005) Placebos and
painkillers: is mind as real as matter? Nature
Reviews Neuroscience 6:
545-552. doi: 10.1038/nrn1705 accessed 20/11/2017


– Ted Med 2014: Published 1 July 2015 accessed 30/11/2017

8Mead E. The magic of the
2017. (accessed 6
Dec 2017).

9 Colloca L, Benedetti F (2005) Placebos and
painkillers: is mind as real as matter? Nature
Reviews Neuroscience 6:
545-552. doi: 10.1038/nrn1705 accessed 20/11/2017

2012 –   ACCESSED 20/10/2017



11 Benedetti, F. Placebo
Effects: Understanding the mechanisms in health and disease (Oxford Univ. Press, 2008) – accessed 20/11/2017




para 2 figure accessed 20/11/2017

13 Benedetti,
F. Placebo
Effects: Understanding the mechanisms in health and disease (Oxford Univ. Press, 2008) – accessed 20/11/2017

14 Placebo and the New Physiology of the Doctor-Patient
Relationship, Fabrizio BenedettiPhysiological Reviews Published 1 July 2013 Vol. 93 no. 3, 1207-1246 DOI: 10.1152/physrev.00043.2012,
figure …accessed 20/11/2017

15 Benedetti  – para 6, 7, 8 and 9 accessed 20/11/2017

16Linde C et al. (1999) Placebo effect of
pacemaker implantation in obstructive hypertrophic cardiomyopathy. PIC study
group. Pacing in cardiomyopathy. American Journal of
Cardiology 15: 903-907. doi: 10.1016/S0002-9149(98)01065-0 (Linde et al. 1999) accessed 30/11/2017




I'm Harold!

Would you like to get a custom essay? How about receiving a customized one?

Check it out