Placebos and the Placebo Effect

The word placebo is derived from Latin and means “I shall please”. We apply the word
placebo to anything that is used with the intent to deceive the recipient. In other words,
placebos have no actual effect but we want the person to believe that the substance will
help them. Placebos are used extensively in medical research to test the efficacy of the
drug being tested. Stated another way, to test the efficacy of a drug (or other
treatment), random volunteers are given the actual drug or a placebo that does not
contain the drug but looks just like the drug being tested. These studies are done blind,
meaning that the people involved do not know which drug is real and which drug is the
placebo. It is expected that this sort of blind testing will prove if the drug actually works
or not. The reason for including a placebo is that it was discovered early on in research
that if the person believes that a treatment will help them, even if it contains only sugar,
in many cases, it does! This phenomenon is called the placebo effect. The place of a
placebo in research is to allow the researchers to then differentiate what is “placebo
effect” and what is the real effect of the treatment.

The magnitude of the placebo effect depends on many factors including:

1. The personal beliefs and expectations of the person receiving the placebo
2. Memories about therapies that the person believes have worked in the past
3. Encouraging words given by people in authority such as doctors or other medical
personnel
4. Color, shape, smell, and taste of the placebo
5. Interactions with other people who feel that the placebo treatment was effective
6. The sight of health professionals, hospitals and medical instruments that
reinforce the belief that the placebo is beneficial.

Below are some interesting studies illustrating the belief factors from the list above. See
if you can determine which of the factors were used in each study to “deceive” the
participants.

Caffeine Placebo: In a study testing sleep deprived students, Anderson and Home,
(2008) demonstrated that the students experienced increased mental performance,
increased reaction time and felt better if they thought they were drinking caffeinated
coffee. The key word is “thought”. In the study the coffee was actually decaffeinated.
However, if the students were told that the coffee was decaffeinated there were no
improvements.

Alcohol Placebo: In 2003, researchers Assefi and Garry showed that participants who
believed they were drinking alcohol experienced feelings of being drunk and actually
showed impaired judgments. The participants were told that they were drinking vodka,
but in reality were given only tonic water. The researchers took 148 students and split
them into two groups. Half of the students were told they were getting vodka and tonic
water and the other half were told they were just getting the tonic water. The research
was carried out in a bar-like room equipped with bartenders and vodka bottles.
However, in reality, both groups just got plain tonic water. What happened? The group
that believed they were drinking vodka experience memory lapses and some even
showed physical signs of being intoxicated the longer the study went on and the more
water they drank. When told the truth, many students insisted that they were in fact
drinking vodka because they felt drunk.

Sham Surgery Placebo: In 2013, Sihvonen et al., developed a test to see if arthroscopic
knee surgery was an effective way to treat knee pain. Participants with severe knee
arthritis were brought to a surgical center and received actual surgery or a sham
surgery. In a sham surgery the patient undergoes anesthesia and the doctor makes
incision in the knee but never inserts instruments. An incision is made and stitched up
but no surgery was ever done. What do you think the results were? You may have
guessed it, as long as the patient believed they had surgery and underwent the same
recovery period as those who received the surgery they believed it helped. All patients
underwent a knee mobility exercise at the conclusion of the healing time, and there
were no differences between those that received the surgery and those that thought
they had received the surgery. In some cases, those who received the sham surgery felt
better and even performed better on the knee agility exercises!

Placebos without deception: It is widely believed that for a placebo to work there has
to be some type of concealment and the patient has to think they are actually taking a
medication that has been shown to treat their condition. However, in 2010 Kaptchuk et
al., demonstrated that even if the patient is told they are being given a placebo that is
nothing more than a sugar pill, it can still help them if they believe that it will! In this
study, patients with severe irritable bowel syndrome (IBS) were give placebo pills that
were labeled as “placebo pills made of an inert substance, like sugar pills, that have
been shown to produce significant improvement in IBS symptoms through mind-body
self-healing processes”. Even with the disclaimer that the pills were just sugar patients
showed a significant improvement of IBS symptoms. Apparently the part that read “have
been shown to produce significant improvement” was enough to convince the
participants.

So how do placebos work? The effectiveness of a placebo is highly correlated to the

expectation. If the expectation is positive it can heal, if the expectation is negative it will
not heal and can make matters worse. A negative effect from a placebo is called a
nocebo. A placebo that is given to a participant, and told it is a stimulant, will increase
heart rate but a placebo given and told it is a depressant will have opposite effects. If
you take something and are told that it will make you stronger then you will be
stronger. The correlation between belief, perception and expectation dramatically
change the effects of a given placebo. Perhaps most interesting is that the color of the
pill also makes a difference. Bright colored placebo pills work better as stimulants and
soft colored placebos as depressants. In short, how do placebos work? We don’t know,
but the belief in, hence the brain, is at the core of placebo effectiveness.

Are Placebos Ethical? If a placebo has a positive effect on the patient, but to get that
effect, the patient has to deceived, is the placebo okay to use? Some argue that
prescribing a placebo is fake medicine. And yet, ibuprofen cannot be tested in the
United States because the belief that Ibuprofen works makes it 60% more effective. In
addition, pain killers are not as effective if infused secretly, instead they work better if
the patient knows they are receiving the drug. The ethical questions surrounding
placebos can be summarized in two arguments: that placebos should not be used
because it is deceptive, and that placebos should be used because the healing effect is
real. Unfortunately the power of the placebo can easily be exploited by businesses
claiming that their particular supplement works, and in many cases the only thing that
contains the supplement is the label. Consider this research from Newmaster et al., 2013
on the contents of 44 different herbal supplements. They found that product
substitution occurred in 30/44 of the products tested, in other words, the actual herbal
supplement was not found in the product. In addition most of the herbal products
tested were of poor quality, contained a considerable amount of substitution and
contamination. Many of the contaminants found posed serious health risks to
consumers.
How do we validate actual effectiveness? To help validate the “actual” effectiveness of
medicine or supplements, the US government established the Food and Drug
Administration (FDA). The FDA is responsible for protecting and promoting public health
through the regulation and supervision of food safety, dietary supplements, prescription
and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals,
blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED),
cosmetics, animal foods and feed and veterinary products. This oversight is not without
critics who argue that the FDA’s regulatory power and testing causes the approval of
drugs to take too long. They argue that because of the slow process for approval, that
relief of human suffering and potential disease benefits from drugs are being
unnecessarily delayed. However, in 2011, Zuckerman and Brown published a report that
showed that most of the medical devices recalled in the last five years for “serious health
problems or death” had been previously approved by the FDA. In addition, the FDA
approved Vioxx in 1999 which has now been estimated to have contributed to fatal
heart attacks in thousands of Americans. Vioxx has been withdrawn from the market. If
the oversight of the FDA approves products that are harmful for humans, what about
products that contain the disclaimer, “these statements have not been approved by the
FDA”, are they safe? Are they effective? Knowing what you now know about placebos,
how difficult is it to prove the actual effectiveness of a particular medicine or
supplement. If people believe it works is it necessary to prove that it actually works?
Perhaps the most famous placebo is vitamin C and its effect on the common cold. This
myth was first propagated by the Nobel Prize winning scientist Linus Pauling. Pauling
won the Nobel Prize for his work on Quantum Chemistry and Molecular Biology. Pauling
was awarded the Nobel Prize in Chemistry and the Nobel Peace Prize, making him the
only person to be awarded two unshared Nobel Prizes. Perhaps this is why his book
entitled: Vitamin C and the Common Cold, which he published in 1970, received
immediate acceptance from the general population but not the mainstream scientific
community. It would appear that expectation and personal belief (Nobel Prize winner)
being the key ingredients to the effectiveness of the placebo effect has made vitamin C
one of the most widely used supplements for treatment of the common cold, even
though countless scientific studies have shown that it has no benefit in curing a cold.

Now what? How then do we validate the onslaught of products which supposedly claim
to have scientific evidence? Is this important? Experience would tell us that benefits
associated with the placebo effect are variable and limited in potency. To be able to
differentiate actual effect verses the placebo effect is important for the consumer.
Failure to differentiate between the two can distract people from receiving the most
effective treatment for their problem, investment of their time and resources into a less
optimal approach, and in some cases put their trust in a treatment that could actually be
harmful. To combat this very problem an article was published in the journal of Nature
(a highly reputable scientific journal) with 20 tips for identifying scientific claims for
validity. The tips are listed below and in some cases have been shortened from the
original article by Sutherland et al., 2013.

1. Differences and chance cause variation. The real world varies unpredictably.
Science is mostly about discovering what causes the patterns we see. There are
many explanations for such trends, so the main challenge of research is trying to
identify which factor or process is causing the main effect. This challenge is
complicated by the fact that most trends are affected by an innumerable amount
of other factors.
2. Bias is rife. Researchers collecting the results as well as participants in studies
can be influenced by knowing who received treatment. The ideal experiment is
double-blind: neither the participants nor those collecting the data know who
received what.
3. Bigger is usually better for sample size. The average taken from a large
number of observations will usually be more informative than the average taken
from a smaller number of observations. Thus, the effectiveness of a drug
treatment will vary naturally between subjects. Its average efficacy can be more
reliably and accurately estimated from a trial with tens of thousands of
participants than from one with hundreds.
4. Correlation does not imply causation. It is tempting to assume that one pattern
causes another. However, the correlation might be coincidental, or it might be a
result of both patterns being caused by a third factor — a 'confounding' or
'lurking' variable. For example, ecologists at one time believed that poisonous
algae were killing fish in estuaries; it turned out that the algae grew where fish
died. The algae did not cause the deaths.
5. Controls (placebos) are important. A control group is dealt with in exactly the
same way as the experimental group, except that the treatment is not applied.
Without a control, it is difficult to determine whether a given treatment really had
an effect. The control helps researchers to be reasonably sure that there are no
 confounding variables affecting the results. Sometimes people in trials report
positive outcomes because of the context or the person providing the treatment,
or even the color of a tablet. This underlies the importance of comparing
outcomes with a control, such as a tablet without the active ingredient (a
placebo).
6. Randomization avoids bias. Experiments should, wherever possible, allocate
individuals or groups to interventions randomly. Comparing the educational
achievement of children whose parents adopt a health program with that of
children of parents who do not is likely to suffer from bias (for example, better-
educated families might be more likely to join the program). A well-designed
experiment would randomly select some parents to receive the program while
others do not.
7. Seek replication. Results consistent across many studies, replicated on
independent populations, are more likely to be solid. The results of several such
experiments may be combined in a systematic review or a meta-analysis to
provide an overarching view of the topic with potentially much greater statistical
power than any of the individual studies.
8. Scientists are human. Scientists have a vested interest in promoting their work,
often for status and further research funding, although sometimes for direct
financial gain. This can lead to selective reporting of results and occasionally,
exaggeration. Peer review is not infallible: journal editors might favor positive
findings and newsworthiness. Multiple, independent sources of evidence and
replication are much more convincing.
9. Study relevance limits generalizations. The relevance of a study depends on
how much the conditions under which it is done resemble the conditions of the
issue under consideration. For example, there are limits to the generalizations
that one can make from animal or laboratory experiments to humans.
10. Data and overall findings can be dredged or cherry picked. Evidence can be
arranged to support one point of view. For example, if researchers reported an
apparent association between consumption of yoghurt during pregnancy and
subsequent asthma in offspring, one would need to know whether the authors
set out to test this sole hypothesis, or happened across this finding in a huge
data set. Sometimes scientists can be looking for an outcome so hard they can
unintentionally manipulate the data to support their hypothesis. In a more global
perspective, when scientists or nonscientists are trying to summarize the current
 findings on a topic (by summarizing the findings from all the studies done up to
that point), either unintentionally or often intentionally only the studies that
support their point of view are used in the summary. It results in an unbalanced
picture of current state of understanding in that area. This is often a technique
used by those trying to sell a product or convince others of their point of view.
The question to ask is: 'What am I not being told?'

References:

Anderson, C. and Horne, J. A. (2008). Placebo response to caffeine improves reaction

time performance in sleepy people. Hum. Psychopharmacol. Clin. Exp., 23: 333–336.

Assefi SL1, Garry M. (2003). Absolute memory distortions: alcohol placebos influence the
misinformation effect. Psychol Sci. 2003 Jan;14(1):77-80.

Diana M. Zuckerman, Paul Brown, Steven E. Nissen. Medical Device Recalls and the FDA
Approval Process. Arch Intern Med. 2011;171(11):1006-1011.

Kaptchuk TJ1, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, Singer JP,
Kowalczykowski M, Miller FG, Kirsch I, Lembo AJ. Placebos without deception: a
randomized controlled trial in irritable bowel syndrome. PLoS One. 2010 Dec 22;5(12).

Sihvonen R1, Paavola M, Malmivaara A, Itälä A, Joukainen A, Nurmi H, Kalske J, Järvinen

TL; Finnish Degenerative Meniscal Lesion Study (FIDELITY) Group. Arthroscopic partial
meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med. 2013
Dec 26;369(26).

Steven G Newmaster, Meghan Grguric, Dhivya Shanmughanandhan, Sathishkumar

Ramalingam and Subramanyam Ragupathy. DNA barcoding detects contamination and
substitution in North American herbal products. BMC Medicine 2013, 11:222

William J. Sutherland, David Spiegelhalter & Mark Burgman. Policy: Twenty tips for
interpreting scientific claims. 503, 747620, 2013