neurosciencestuff:
How “open-label” placebos turn fake pills into real treatment
This may not sound like a good idea:
Find people in pain.
Enroll them in a study.
Admit you can’t do much to help.
Give them a fake pill.
Tell them that’s exactly what you are doing.
But here’s the crazy thing: It works.
For a large number of participants in these “open-label" placebo
trials, knowing that their “treatment” is an inert pill doesn’t stop
them from feeling relief.
Now, a group of researchers at UAB and Harvard University are taking
these studies into a new patient population: cancer survivors. For men
and women struggling with the crushing fatigue that often emerges in the
years after treatment, the power of placebos may be just what they
need.
Placebo research sounds like an oxymoron. Placebos are the stooges of
medicine, the character in any clinical trial that everyone is rooting
against. But they also have some remarkable properties. “For some
clinical conditions, in anywhere from 30 to 50 percent of clinical
trials, the placebo is just as good as the drug being studied,” said
Teri Hoenemeyer, a doctoral student in health behavior at UAB who is
studying placebo effects in cancer survivors.
Researchers used to assume (and many still do) that this meant the
drug being studied wasn’t any good. But others have produced convincing
evidence that something deeper is going on.
Placebos under the microscope
Ted Kaptchuk, director of the Program in Placebo Studies and the Therapeutic Encounter at
Harvard University and Beth Israel Deaconess Medical Center, and a
professor of medicine at Harvard Medical School, may have done more than
anyone else to reveal the surprising power of placebos. Kaptchuk’s
clever, intriguing studies have drawn national attention, including a
lengthy profile in the New Yorker. His most famous experiment, published in the journal PLOS ONE in 2010,
recruited 80 patients with irritable bowel syndrome, a painful
condition with few available treatments that affects up to 15 percent of
Americans.
One group of participants got no treatment. The other group was given
inert pills, clearly labeled “placebo pills,” and told the medications
were fake. But the researchers also explained that patients often
experience benefit from placebos. To everyone’s surprise, this group
reported twice as much improvement as the untreated control group.
That finding received wide media coverage. A reporter for NPR interviewed a participant
in the trial, who revealed that her symptoms — cramps, bloating,
diarrhea — “went away,” said Kaptchuk. “Some of the patients came back
and asked for more pills.”
The great benefit of an open-label placebo, Kaptchuk said, is that “it’s an honest placebo.” No deception is involved.
An unexpected discovery
“Ted never thought it would produce a benefit,” said Kevin Fontaine, Ph.D., chair of the Department of Health Behavior in the UAB School of Public Health,
who has been interested in Kaptchuk’s placebo research for several
years. “But now he’s done studies with depression and migraine as well.
And in every instance, there’s been a significant benefit.”
At Fontaine’s invitation, Kaptchuk recently visited UAB to give a talk on placebo effects at the Comprehensive Cancer Center.
“The role of placebos and their impact on human health is bigger than
many of us realize,” said Edward Partridge, M.D., the center’s director,
in introducing Kaptchuk. “I think he’s really onto something important,
and it will move into mainstream medicine.”
Fontaine feels the same way. “I’m fascinated with the topic,” he
said, “but also with trying to find creative ways to affect symptoms.
The burden of things like fatigue and pain on quality of life is
extremely high, and we just don’t have effective treatments. So if we
can take advantage of this phenomenon in a way that produces benefits to
patients, that is my primary motivation.”
Hoenemeyer, who is director of education and supportive services at
the Cancer Center as well as Fontaine’s graduate student, decided to
focus on the open-label placebo concept in cancer survivors for her
doctoral thesis. Kaptchuk, who now holds an adjunct faculty appointment
at UAB, is acting as a consultant on the study and an advisory member of
Hoenemeyer’s dissertation committee.
“People who have survived cancer, no matter which type, often
experience a penetrating fatigue that seems to go on indefinitely,”
Fontaine said. “It really compromises the quality of their lives, and
currently there are no effective treatments.”
Battling cancer fatigue
This summer, Hoenemeyer hopes to begin enrolling patients in the
first study of an open-label placebo in cancer. The seven-week trial
will be open to cancer survivors who have completed treatments for at
least six months, and are experiencing at least moderate levels of
cancer-related fatigue. “We want to see if we can make any difference in
symptom severity,” Hoenemeyer said.
Participants will be divided into two groups; for the first two
weeks, one group will receive the placebo pill while the second acts as a
control. Then, after a weeklong “wash-out” period, they will switch
places. “Wash-out” time is common in drug studies, when investigators
want to give participants time to clear one medication out of their
system before starting another. “Believe it or not, that seems to be
important in placebo trials as well,” Hoenemeyer said.
The researchers will be looking at intra-group and inter-group
differences. They will also collect saliva samples from all participants
and analyze these samples for evidence of a potential genetic biomarker
of response. Previous studies by one of Kaptchuk’s students at Harvard
have found preliminary evidence of a genetic predisposition in patients
who respond well to placebos.
Such biomarkers would be extremely interesting to pharmaceutical
companies, Fontaine explains. They could use it to weed out participants
from clinical trials of new drugs who would be more likely to have a
positive response no matter what treatment they get.
In 2013, Fontaine, Kaptchuk and Gareth Dutton, Ph.D., a colleague in UAB’s Division of Preventive Medicine,
sought funding from the National Institutes of Health to apply the
open-label approach to see if it would help people lose weight. “All of
the patients would get a diet and exercise program,” Fontaine explained,
“but half of them would also be asked to take open-label placebo
pills.” The researchers would then see whether or not the pill-taking
group lost more weight. “The interesting thing about this study is it
would produce objective outcomes — weight loss, body composition, and
physical activity — instead of just reported symptoms, and quality of
life,” Fontaine said.
Although the grant received a perfect peer review score, it was not
funded. “We were told that the study moves us too far beyond what we
currently understand about placebo effects,” Fontaine said.
Studies such as the UAB cancer trial, and other work ongoing in
Kaptchuk’s lab at Harvard, are attempting to advance our understanding
of those placebo effects.
How it could work
So how could an inert pill be affecting the body? Kaptchuk and other researchers are exploring several different possibilities.
“We believe there’s some element of classical conditioning going on,”
Fontaine said. “Throughout your life, you take a pill and you see an
effect. You take an aspirin, for instance, and it takes away your
headache. There’s an association there in your mind, and the idea is
that the ritual of taking pills may actually produce a beneficial
effect.”
Consider, Fontaine said, that “effective treatments have really only
been around for the past century.” Before then, he continued, “the
physician, or the healer, had to be able to alter a patient’s
perceptions, change their expectations or create benefits even when he
or she couldn’t tangibly give anything that was beneficial.”
Placebo responses could also be a matter of expectations. “Part of
the intervention when we give the placebo pills is to create a rationale
for why they might work,” Fontaine said. “We talk about all the studies
that have shown an effect, so the person begins to develop an
expectation that if I take these pills I’m going to have a beneficial
effect.” That is what happens routinely in clinical care, Fontaine
points out. “When a physician sits down with a patient and writes a
prescription, the patient’s expectation is this is going to help.”
Another idea, “one that Ted is particularly keen on,” Fontaine said,
is the role of “nonconscious mechanisms.” If you go to a horror movie,
for example, “you know it’s not real, and yet you have a physiologic
response,” said Fontaine. (“The brain has been called a prediction
machine,” Kaptchuk said.) Somehow, Fontaine explained, “taking the pills
may engage the imagination and simulate a therapeutic response.”
Interestingly, people with Alzheimer’s disease don’t seem to have a
placebo response, Fontaine says. “That could be because the prefrontal
cortex has been impaired, so they can’t develop the expectation, or they
are not aware of it.”
At this point, however, “I’m less concerned with the mechanism than
with whether or not it actually has a benefit,” Fontaine said. “If it
does, then we can try to figure out the mechanism.”