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| Journal of the New Zealand Medical Association,
09-April-2010, Vol 123 No 1312
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Physiology of the placebo effect, and the evidence
for changes in brain metabolism
Martin Wallace
(This paper is based on a presentation to the NZ
Skeptics’ Conference, 2008)
Early in 2008, Dr Tipu Aamir of the Auckland Pain Management
Service drew my attention to the following. In a double-blind, randomised,
placebo-controlled trial of morphine after a standard knee operation, 30% of
those receiving a placebo get pain relief. When those people are given a
specific morphine antagonist (“antidote”), their pain comes
back!
My excited reaction had all the hallmarks of an epiphany. I
needed to know more. After all, how could something that was “all in the
mind” be changed predictably by a substance with a known pharmacological
action?
Any study of homeopathy raises the issue of the placebo
effect. As a result of a meta-analysis of a number of studies comparing
homeopathic remedies with orthodox treatment, it was concluded that the effect
of homeopathic remedies was no greater than that of a
placebo.1 Not that they had no effect, but that
it was no greater than that of a placebo.
Sceptical thinkers are often happy to accept the explanation
that if a response to some arcane practice is a placebo response, then that
settles the issue.
Over the last 30 years there has been a large amount of
research into the (undoubted) effects of placebos. I was unaware of the results
of this activity and the light they shed on our nature. I thought it might be of
interest to review this work, and our frequent use of “placebo
effect” to explain the unscientific.
Placebo is a Latin word for “I shall be
pleasing”, or “acceptable”. It is the first word of the first
antiphon of the Roman Rite of the Vespers for the Dead, “Placebo
Domino”. (Dating from the 7/9th Centuries
of the current era). Chaucer called one of his characters Placebo in the
Merchant’s Tale, because by the 14th
Century, it had come to mean a flatterer, a sycophant, or a
parasite.2
“Placebo
seyde:
Ful little need had ye, my lord so deare, Council to ask, of any that are here But that ye be so ful of sapience.” He also used it in the Parson’s tale:
“Flatterers be the Devil’s chaplains, which sing ever
‘Placebo’”
In the 1811 edition of Hooper’s Medical Dictionary,
placebo was defined as “an epithet for any medicine adopted more to please
than benefit the patient”. In a recent edition of “Collins’
Concise Dictionary of the English Language” it is defined as “an
inactive substance administered to a patient to compare its effects with those
of a real drug, but sometimes for the psychological benefit of the patient
through his believing he is receiving treatment”. However, placebos do
benefit patients, and they are certainly not inactive in the context in which
they are given.
The most dramatic example of this that I saw in clinical
practice involved a young man on artificial kidney treatment. When
erythropoietin became available for the treatment of the severe anaemia seen so
often in this situation, he was the first patient in our unit to receive
it.(Erythropoietin is a hormone made in the healthy kidney, which increases the
number of red cells in the blood and the amount of the oxygen carrying
haemoglobin. The synthetic version has achieved notoriety as a performance
enhancer in sport; for example in the “Tour de France”.)
We were all very enthusiastic about this improvement in
management for our patient, and he was given his first dose with much interest
from all of us. That night he went home, recovered his bicycle from the shed
where it had been undisturbed for many months, and rode all around his town with
great energy and pleasure. He hadn’t heard the information that the drug
took 3 weeks to act on the anaemia.
We are left with some questions. What was the physiology of
his sudden ability to exercise at a “normal” rate, long before there
was any change in his blood count? What does “its all in the mind”
mean? Was he somehow at fault, or was it me and the staff who were lacking in
understanding?
I would like to consider:
Psychological mechanismsThose who study the psychological processes of the placebo
effect, cite two major mechanisms.
Conditioning—Pavlov (1849–1936)
showed that dogs given meals as a bell rang would subsequently salivate when the
bell rang despite not being given food. This process has been explored in
humans, who will experience pain relief when a placebo is substituted for a pain
reliever when a sequence of active analgesia has been associated with an
environmental cue. It is an unconscious process. At the nerve cell level,
conditioning leads to a stronger and more sustained response.
3
Expectancy—This effect is seen when
the patient has “great expectations” of the substance being given.
These are raised by the conscious or unconscious attitude of the therapist. It
is a conscious process on the part of the patient.
It is currently suggested that both conditioning and
expectancy are active in the placebo effect, and that in fact, as an inert
placebo can have no effect per se; what we see is the effect of the
context in which the treatment is given.
Neurophysiology of placebo pain reliefOver the last 30 years, there has been much interest in the
neuro-physiological mechanisms of the placebo response.
In 1975, two related pentapeptides (a chain of five amino
acids linked together) with potent opium-like action were identified in the
brain. 4 Many more have been identified since.
These compounds act on specific receptors on the membranes of neurones, and via
intracellular metabolic changes increase synaptic transmission. They are made in
the pituitary and hypothalamus, and are called endorphins.
A digression...
In pharmacology the term agonist denotes a drug with an
effect, and antagonist, a drug which specifically blocks the effect of the first
substance.
When I spent a year in the pharmacology lab in Dunedin
(1959) it was becoming recognised that drugs exerted their effects by way of a
specific receptor molecule at the cell surface. The actions of adrenaline, for
example, were explained by the presence of two different molecules to which it
could attach, which mediated different effects. Noradrenaline would latch on to
only one, explaining its more limited range of action.
With their usual desire for learned coherency,
pharmacologists called them alpha and beta receptors. Antagonist molecules
attach to the receptor molecule and block access by the agonist. Hence the term
“beta-blockers.” These are substances which block the action of
adrenaline on its beta receptor. They are widely known for their action in the
control of blood pressure, and recently for their unwanted effects when given to
protect patients at risk of heart trouble when undergoing operations.
Agonists and antagonists are related by similarities in
molecular size, shape, and charge. Morphine antagonists have been available for
some time. In 1961 as a house-surgeon in casualty, I was asked to manage an
opium addict, brought in because he was deeply unconscious, and breathing
perhaps once a minute. (He had been without drug for some weeks, due to market
fluctuations. When access was resumed, he used a dose which was the same as his
habituated dose. This was much more than he could now tolerate.)
I had access to nalorphine, a specific morphine antagonist,
and 30 seconds after an IV injection, the patient took several deep breaths, sat
up, expressed considerable surprise at his surroundings, and then lapsed back
into his former state. I was able to repeat this dramatic procedure several
times until he recovered!
In 1978 a group of dental surgeons working in California
carried out the following experiment.5 Patients
who had had an impacted wisdom tooth extracted were treated routinely with
nitrous oxide, diazepam and a local anaesthetic. At 3 hours after the procedure
they were given either a placebo or naloxone (a specific morphine antagonist).
At 4 hours they were given a placebo or naloxone. Those who had initial pain
relief with the first dose of placebo (39%), when given naloxone had an increase
in pain.
The authors concluded that “this was consistent with
the hypothesis that endorphin release mediates placebo analgesia in dental
postoperative pain.”
The elegance of this study lies in the unequivocal evidence
that a supposedly psychological state (placebo analgesia) was reversed by a
specific opioid antagonist. Note that none of the patients was given morphine.
There must be a physiological cause for placebo analgesia.
This sort of study has been repeated many times, and always
naloxone reverses placebo analgesia.
The site of action of opioids in the brainThe site of this process has been determined. The sites for
opioid receptors in the brain can be found by specific cell staining methods and
histology on brain tissue. But more exact, “real-time” evidence
comes from PET scans.
Another digression...
Positron emission tomography utilises short half-life
radioactive elements which undergo spontaneous beta decay. In the process, they
emit a positron, which collides with an adjacent electron resulting in mutual
annihilation, and the generation of two high-energy photons at a nearly 180
degree angle. These can be detected, and with many, many such events, used to
build up a tomographic picture of the source in relation to surrounding tissue.
In the studies of the brain, radioactively-labelled glucose
is injected, and congregates where activity (utilisation) is greatest. PET scans
are used to monitor metabolic activity in specific organs. For example, the
extent of heart muscle damage after a heart attack.
In 2002, it was shown that both opioid and placebo analgesia
are associated with increased brain activity in specific regions: the anterior
cingulate cortex (ACC) and the brain stem. 6
There was no increase of activity in these regions with pain only.
Similar localised brain activity has been shown in placebo
responses in Parkinsonism (dopamine) and some depressive states
(serotonin).
I find these studies exciting and provocative.
Genetic predilectionA further question can be asked in the light of the evidence
for a physiological mechanism for the placebo effect. Why does it occur in
only30—40% of us for a given situation? It may occur in a greater
proportion of a population sample if the context is made more convincing. But
why don’t we all have the benefits? Variation in a physiological function
begs the question of a genetic predilection.
Individual differences in suggestibility contribute
significantly to the magnitude of placebo analgesia.
7 The higher the suggestibility score (there
are several tests available) the greater the placebo analgesic effect.
As early as 1970, it was shown that there was a correlation
of suggestibility between monozygotic twins but not dizygotic (fraternal)
twins.8 (Monozygotic twins are the result of
the fertilisation of one ovum by one sperm. The resulting zygote splits into two
cells which each develop into an individual. These individuals have exactly the
same genes of course.)
There is a relationship between hypnotic susceptibility and
familial handedness. 9 Subjects with left
handed (sinistral) close relatives scored lower in a test for hypnotic
susceptibility.
A number of studies have been carried out on twins who for a
variety of reasons, were reared apart. 10
Correlations between identical twins (monozygotic) and between fraternal twins
(dizygotic) have been done and compared. The studies from this group (in
Minnesota) have shown a large group of correlations in identical twins reared
apart, which do not occur in fraternal twins reared apart.
The correlations differ very significantly. Here are some
examples in twins reared apart:
Similar studies have given similar results in Australia and
Western Europe.
Because the nurture of these twins is different, and
identical twins have identical genes, the similarities must be genetic. This
approach to behaviour has lead to the science of “behaviour
genetics”. (Physical attributes are of course also correlated more between
identical twins reared apart, than fraternal twins reared apart.)
A group in New York State have shown that a genetic
polymorphism (more than one version of a specific gene) exists for a gene on
chromosome 22, which codes for an enzyme active in the breakdown of dopamine, a
neurotransmitter.11 One amino acid substitution
(valine for methionine) in the gene alters the enzyme activity by a factor of
four times.
Since we have a copy of this gene from each parent, we may
have val/val, or val/meth, or meth/meth genotypes:
Brain pathways in which opioid
receptors are active are linked to those in which dopamine is the transmitter
(nerve to nerve). If there is genetically conferred variation in dopamine
activity it is likely that this will influence the result of changes in activity
in the opioid pathways.
(We must remember that we are talking of a genetic
predisposition to be suggestible, and not a gene for suggestibility. It is not
that 69% of identical twins vote Republican, but that if one does there is a 69%
probability that the other one does too.)
The implications for drug trialsThe open / hidden model for drug trials:
A group in Turin have examined pain relief in patients after
thoracotomy.12 Patients were allocated to
either open infusions of morphine, with information about the efficacy of the
drug, or to receive hidden doses of morphine by infusion without any information
and without any doctor or nurse present. With the same dose, same infusion rate,
same timing and same drug, pain relief was less in the “hidden”
group.
In the “open” group, the
“meaning-induced” expectations had enhanced the drug effect. This
group and others have gone on to postulate that in all drug treatment the effect
is the sum of actual physiological effect plus the effect of
expectations.13 This means that the placebo
effect will always cause part of the usual “physiological” response
to active drugs.
They say that the classical double blind randomized placebo
controlled trial does not allow for expectation effects, and may suggest that a
drug has a specific effect greater than it actually has. They suggest an
“open/hidden paradigm” will give more meaningful results.
Conclusions
We have come a long way from the Vespers
for the Dead!
Placebos are inert substances but the context in which they
are given can alter neurophysiology in such a way as to cause subjective
and objective effects.
This is not due to the “molecular memory” of
water, nor to strange force-fields as yet unknown to physicists. It is due to
our human nature, how we react to our environment, and the relationship, between
our minds and our bodies.
Competing interests: None known.
Author information: Martin Wallace, Retired
Renal Physician, Hamilton
Correspondence: Martin Wallace, 24
Stonebridge Estate, Wallace Road, R D 9, Hamilton 3289, New Zealand. Email: mart-jan@xtra.co.nz
References:
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