Download Placebos and the Placebo Effects

Placebos and the
Placebo Effects
What they are and why we should
love them
© Heidi Most, M. Ac, L.Ac, Dipl Ac (NCCAOM)
Your body’s ability to heal is
greater than anyone has
permitted you to believe.
“Always the purpose of
treatment is only to restore
nature’s balance against
disease. There is no recovery
unless it comes from the force
and fiber of one’s own tissues.”
Dr. Sherwin Nuland, Yale University School of Medicine, Cliinical Professor of Surgery
Purpose of this lecture

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Learn that the context in which treatment
is given, and the patient’s and the
practitioner’s beliefs, play a major role in
the patient’s response to treatment
Change the question of concern from “are
placebos ethical?” to “how can we make
our treatments most effective.”
Why is this important?

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We want to be the best clinicians possible
Given the crisis in health care costs, we
need to be including all possible methods
of increasing effectiveness without
increasing cost.
Definition of placebo?
What is the placebo effect?
Working definitions
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Placebo: “An intervention designed to simulate
medical therapy that at the time of use is
believed not to be a specific therapy for the
condition for which it is offered.
Placebo Effect: “A change in a patient’s illness
attributable to the symbolic import of a
treatment rather than a specific pharmacologic
or physiologic property.

Brody H. Placebos and the Philosophy of Medicine. Clinical, Conceptual, and Ethical
Issues. Chicago: University of Chicago Press, 1980
How does the placebo effect
occur?
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Psychological mechanisms which contribute:
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Expectations
Conditioning
Therapeutic and Social Relationships
Motivation
Neuro-biological mechanisms
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Endorphin release
Brain changes
Expectancy
Expectancy
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Research subjects receive experimentally
induced pain and are given a topical
placebo cream in the context of two
different cues:
1) the cream is inert and will have no effect
2) the cream is a powerful pain killer
Verbal cues can manipulate
expectations and mediate
placebo effects:
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Analgesic effects (both experimentally and
clinically)
Changes in motor performance in
Parkinson’s disease patients
Changes in emotions and brain responses
“Expectancy” research:
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Research on post-operative pain divided
patients into three sections
1)
2)
3)
Received morphine secretly
Received morphine and were told they were
Received placebo but told it was a powerful
pain reliever
Results:
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Patients who were told they received a pain reliever,
whether they actually received it or not, had the same
experience as those who secretly received between
six and 8 milligrams of morphine.
The covert dose had to be increased to 12 milligrams
to surpass the effect of the placebo
Levine JD, Gordon NC Analgesic responses to morphine and placebo in individuals with
postoperative pain Pain, Vol 3, 1981
More “Expectancy” research:
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Diazepam has no discernible effect on anxiety
unless a person knows he is taking it. Luana Colloca, Leonardo
Lopiano, Michele Lanotte, Fabrizio Benedetti Overt versus covert treatment for pain, anxiety, and Parkinson's disease The
Lancet Neurology, Volume 3, Issue 11, November 2004, Pages 679-684

In double blind studies of anti-depressants,
patients often figure out if they are getting the
“real drug” by side effects. The worse the side
effects, the more effective the drug.
Classical Conditioning
Classical Conditioning

Repeated associations between a neutral
stimulus and an active drug can result in
the ability of the neutral stimulus by itself
to elicit a response characteristic of the
drug

Responses include changes in hormone
secretions and immune response
How does a conscious or
unconscious thought
translate into action?
Thinking a thought,
believing a belief, causes
biological reactions
The Limbic System
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Consists of many
different sub-areas,
with neuronal
connections to each
other and especially
to the hypothalamus
Prefrontal cortex has
many connections to
it
The hypothalamus sends
messages to the rest of the
body through the ANS and
the Endocrine system.
Therapeutic and Social
Relationships
Therapeutic and Social
Relationships
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Results of two randomized control trials
with asthma patients and with rheumatoid
arthritis patients
Active group: patients described a
significantly difficult conflict or secret about
past traumas to the clinician
Control group, patients talked about
superficial things
Smyth, J., Stone, A., Hurewitz, A & Kaell, A. 1999 Effects of writing
about stressful experience on symptom reduction…JAMA 281 1304-1309
Result

At the 4 month follow-up, asthma patients
who were in the active group showed
significant improvements in forced
expiratory volume, and those with arthritis
showed significant improvements in pain,
when compared with their control groups.
More relationship research
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Large RCT showed that a positive
consultation by a physician produced 2025% greater improvements in functional
conditions compared with a negative
consultation. Amount of time spent in
consultation was equal.
Extensive summaries of this research: Chez,
R.A & Jonas, W. 2005 Developing healing relationships: J. Altern.
Complementary Med. 11, S1-S2 and Safran, D., Miller, W. & Beckman H.
2006 Organizational dimensions of relationship-centered care: …J. Gen.
Intern Med. 21, S9-S15.
Neuro-biological mechanisms
Neurobiological mechanisms
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Placebo analgesia: The suggestion that a
substance will reduce pain increases the
release of endorphins, which make
patients feel less pain
When given Naloxone, which lock up key
opioid receptors, the pain comes back
Fields HL,
Levine JD. Placebo analgesia- a role for endorphins. Trends in Neuroscience 1984; 7:271-73
Other biological effects:
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Placebo analgesic effects are inhibited by
the peptide CCK
Several studies have demonstrated highly
specific endogenous opioid-mediated
placebo analgesic responses, such as
increased opioids in cerebrospinal fluid
PET and fMRI show placebo induced brain
changes mirror those found in opioid drug
administration.
The effects are not limited to
analgesia
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Increase in respiratory functioning
Decreased heart rate
Dopamine release and changes in basal
ganglia and thalamic neuron firing in
Parkinson patients
Can see changes in metabolic activity in
the brain in depression and expectation
manipulation with addiction
Albuterol Trial
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Double-blind crossover study of 46
patients with asthma
Wechsler, M, Kelley J, Boyd, OE, Dutile, S,
Marigowda G, Kirsch I, Israel E. Kaptchuk, T. “Active Albuterol or Placebo, Sham Acupuncture, or
No Intervention in Asthma, N Engl J Med 2011;365:119-26
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4 arms
 Active
treatment (albuterol inhaler)
 Placebo inhaler
 Sham acupuncture
 No intervention
Methods
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Administered one each of the four interventions
in random order during four sequential visits (3-7
days apart).
Procedure repeated in 2 more blocks of visits for
total of 12 visits for each patient
Spirometry was performed repeatedly over a
period of 2 hours, and patients’ self-reported
improvement ratings were recorded
Results
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Albuterol resulted in a 20% increase in
FEV1, as compared to 7% with each of the
other three interventions
Patients reported equal and substantial
improvement with the inhaled albuterol,
inhaled sham and the sham acupuncture.
QuickTime™ and a
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QuickTime™ and a
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Discussion
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Findings consistent with meta-analysis
involving multiple conditions, where
placebos, as compared with nointervention controls had no significant
effect on objective measures but did have
significant effects on subjective outcomes.
Hrobjartsson A, Gotzshe PC. Is the Placebo powerless? An analysis of clinical trials comparing placebo with no
treatment. N.Engl J Med 2001;344;1594-602
Discussion cont’d
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Findings do not contradict recent lab
studies showing that placebo treatment
elicits quantifiable changes in
neurotransmitters and regionally specific
brain activity that influence symptoms.
Bifurcation of effects may represent
difference between treating disease and
treating illness.
When is there no placebo
effect?
Loss of placebo mechanisms
reduce therapeutic efficacy
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In an open-hidden design in Alzheimer’s
disease, the placebo component was
correlated with cognitive status and
functional connectivity between brain
regions.
The lower the cognition and connectivity
the less the analgesic effect, to the point
where an increase in dose was required
for same level of analgesia.
Benedetti F, Arduino C, Costa S,
Vighetti S, Tarenzi L, Rainero I, et al. Loss of expectation-related mechanisms in Alzheimer’s disease makes
analgesic therapies less effective. Pain 2006 Mar
So far, what do we know?
Limitations in current
research
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Most have involved lab experiments over
short durations with healthy subjects
Longer term placebo response has been
studied in RCTs; but these rarely include
no treatment groups to control for natural
history and regression to the mean
More research is needed from a basic
science, clinical trial and ethical
perspectives
Some specific placebo
research
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3 week single blind RCT with IBS patients
(n=262)looked at sham acupuncture, sham
acupuncture plus supportive patient-practitioner
relationship compared to no treatment control.
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62% adequate relief (AR) with acu + support
44% AR acu alone
28% AR no treatment
Kaptchuk Tj, Kelley JM, Conboy,LA, Davis RB, Kerr CE, Jacobson EE, et al. Components of placebo effect; randomised controlled trial
in patients with IBS. BMJ 2008 May 3
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Different vehicles of placebo
ritual produce different
effects
Sham acu more effective than pills in
ability to function
Depending on complaint and length of
time administered, different placebos had
different effects
Different nocebo effects also observed
Alternative therapies with
elaborate rituals have
clinically significant placebo
effects
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Large acu trials in Germany compared acu,
sham acu, usual care, and no treatment for
migraine, tension HA, chronic LBP, and OA of
the knee
Verum and sham acu resulted in substantially
greater symptom improvement than no
treatment and usual care.
More on the German studies
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Positive expectations influenced analgesic
responses, doubling the likelihood of
positive outcomes.
Results lasted one year.
Other interesting findings:
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The larger the pill, the stronger the
placebo effect
Two pills are better than one
Brand name pills are better than generics
Capsules are more effective than pills
Injections produce more pronounced effect
that capsules or pills
More interesting findings:
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Colored pills are more likely to relieve pain
than white pills
Blue pills help people sleep better than red
pills
Green capsules work best for anxiety
medication
Surgery is an extremely
powerful placebo
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Treatment for coronary artery disease in
the 1950s (bilateral internal mammary artery ligation BIMAL) was
found to be no better than placebo surgery
(relief from angina was significant in 7080% of patients in both active and sham
treatment
At same time as this research, heart lung
bypass machine was developed, allowing
for coronary artery bypass surgery.
Results:
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Coronary artery bypass surgery has never
been tested in a placebo-controlled trial
Its effectiveness in treating angina is
approximately the same as the old
treatment: 70-80%
More placebo surgery
research
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Placebo-controlled study of 298 patients
with class III or IV heart failure underwent
high-dose laser treatment, low-dose laser
treatment or placebo (catheter inserted but
the laser was never turned on)
Equally significant improvement in all
groups which lasted over 6 months.
Johnson A.
1994 Surgery as placebo. Lancet 344, 1140-1142
More placebo surgery
research
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The placebo “debridement” of
osteoarthritis with arthroscopic surgery
showed just as good pain relief as actual
debridement for the same procedure.
Two control conditions:
Only laparoscopic lavage was used
 Skin incision made without insertion of
laparoscope
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Results:
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Pain relief lasted over 2 years and was
equal in all groups.
Moseley, J., O’Malley, K., Petersen, N., Menke, T., Brody, B.,
Kykendall, D., Hollingsworth, J., Ashton, C., and Wray, N. 2002 A controlled trial of arthroscopic surgery for OA of
the knee. N. England J. Med 347, 81-88
Placebo effects are inherent
in clinical practice, even w/o
placebo
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Hidden administration of 5 commonly
used painkillers were markedly less
effective than open administration
Colloca L,
Lopiano L, Lnotte M, Benedetti F. Overt versus covert treatment for pain, anxiety, and Parkinson’s disease. La cet Neurology
2004; 3; Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to analgesics: a role for non-specific activation of
endogenous opiods. Pain 2001;
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Similar results have been reproduced
for drug admin for anxiety and deep
brain stimulation for Parkinson’s
Disease
Another open-hidden
paradigm study
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CCK antagonist proglumide was shown to be
better than placebo, which was in turn better
than no-treatment for post-operative pain.
However, a hidden injection of proglumide was
completely ineffective, showing the drug
achieved a response by interacting with and
enhancing the expectancy pathways.
Its effectiveness was dependent on the placebo
mechanisms inherent in the clinical encounter.
Benedetti F, Amanzio M, Maggi G. Potentiation of placebo analgesia by proglumide. Lancet 1995d
The placebo effect is not
always present
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Placebos are not magic
They have not been proven to be effective
in reducing tumors, changing the course of
fatal diseases, reducing extremely high
levels of pain…
AND
we can improve many
therapies through using the
placebo effect.
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A short term experiment in 2001, postoperative pain patients took 33% less active
analgesic if they believed they were also
receiving intravenous analgesia.
Pollo A, Amanzio M, Arslanian A,
Casadio C, Maggi G, Benedetti F. Response expectancies in placebo analgesia and their clinical relevance.
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Ain 2001; 93 (1)
In IBS study, patients exposed to a painful
stimulus under two conditions: local
anesthetic and placebo. In one study they
were told that they “may receive an active or
a placebo agent” and in the second they
were told that “the agent you have been given
is known to significantly reduce pain in some
patients”. Placebo responses were larger in
the second study.
We have seen expectation
and belief strongly influence
therapeutic outcomes.
In what other unconscious
ways is our behavior
influenced?
Other ways our behavior is
unconsciously influenced:
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Marketing (wine labeled from CA tastes better
than wine labeled from IN, even though it is
the same wine)
Embodied cognition: our rationality is
influenced by our bodies (women who wore
bikinis did worse on math tests)
Enclothed cognition (the clothes we wear
influence how we experience the world)
How can we maximize the
therapeutic effects of our
treatments?
The definition of treatment
needs to be broadened
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Drugs
Surgery
What we say
How we conduct ourselves
The environment in which we work and
see patients
Therapeutic relationships
Reminder:
Placebo is an intervention
designed to simulate
medical therapy that at the
time of use is believed not
to be a specific therapy for
the condition for which it is
offered.
Important to recognize what
we don’t know
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We do not know the limits of our knowledge, of
our own minds
“The scientist knows that in the history of ideas,
magic always precedes science, that the
intuition of phenomena anticipates their
objective knowledge.”
“Advance in detail is permitted: fundamental
novelty is barred. This dogmatic common sense
is the death of philosophical adventure.”
Gauguelin 1974
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Alfred North
Whitehead (1948)
What we think of as
placebos might in fact be
proven in the future to have
specific therapeutic effects.
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Acupuncture
Reiki
Therapeutic touch
Bio-feedback
What else do we know of
that strongly influences
therapeutic outcomes?
Mindfulness-based Stress
Reduction
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Conscious relaxation reduces the cascade
of stress responses, reducing our heart
rate, blood pressure, relaxing our bowels,
improving digestion, reducing pain in
chronic disease, makes learning easier
Our immune system responses are
improved, we get less colds, miss fewer
days of work
What are the ethical
considerations?
If treatments have not been
successful, or as successful
as you would like, is it
ethical to:

Recommend
acupuncture?
 meditation?
 herbal preparations?
 Bio-feedback?
 Crystal therapy?
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What level of information do
you need to make a
recommendation?
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Double blind RCTs? How many?
Other forms of research?
Good friends, family members who
have benefited?
What level of information is enough?
Summary
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A patient’s expectations, beliefs,
conditioning and anxiety can strongly
effect treatment efficacy
As practitioners, we can strongly affect
those expectations through our words, and
behavior.
We can use the evidence from placebo
research in a way that is ethically
acceptable and effective.
Recommendations
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Wayne Jonas
Replace the term Placebo Effect with
concepts such as “meaning and context’
response components in research
Create optimal healing environments for
all of our clinical care
Acknowledgements:
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“Placebo Effects: Biological, Clinical and
Ethical Advances” Damien G Finniss, Ted
J. Kaptchuk, Franlin Miller and Fabrizio
Benedetti, Lancet. 2010 February 20;
“Reframing Placebo in Research and
Practice” Wayne B. Jonas, Philosophical
Transactions of the Royal Society 2011