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Features
The Placebo Phenomenon
An ingenious researcher finds the real ingredients of “fake” medicine.
Research
* Photograph by Jim HarrisonTed Kaptchuk in his home office in
Cambridge
Print | PDF | Reprints
by Cara Feinberg
January-February 2013
Email
Keywords
Harvard Medical School, health and medicine, placebos, Ted Kaptchuk
Two weeks into Ted Kaptchuk’s first randomized clinical drug trial,
nearly a third of his 270 subjects complained of awful side effects.
All the patients had joined the study hoping to alleviate severe arm
pain: carpal tunnel, tendinitis, chronic pain in the elbow, shoulder,
wrist. In one part of the study, half the subjects received
pain-reducing pills; the others were offered acupuncture treatments.
And in both cases, people began to call in, saying they couldn’t get
out of bed. The pills were making them sluggish, the needles caused
swelling and redness; some patients’ pain ballooned to nightmarish
levels. “The side effects were simply amazing,” Kaptchuk explains;
curiously, they were exactly what patients had been warned their
treatment might produce. But even more astounding, most of the other
patients reported real relief, and those who received acupuncture felt
even better than those on the anti-pain pill. These were exceptional
findings: no one had ever proven that acupuncture worked better than
painkillers. But Kaptchuk’s study didn’t prove it, either. The pills
his team had given patients were actually made of cornstarch; the
“acupuncture” needles were retractable shams that never pierced the
skin. The study wasn’t aimed at comparing two treatments. It was
designed to compare two fakes.
Although Kaptchuk, an associate professor of medicine, has spent his
career studying these mysterious human reactions, he doesn’t argue that
you can simply “think yourself better.” “Sham treatment won’t shrink
tumors or cure viruses,” he says.
But researchers have found that placebo treatments—interventions with
no active drug ingredients—can stimulate real physiological responses,
from changes in heart rate and blood pressure to chemical activity in
the brain, in cases involving pain, depression, anxiety, fatigue, and
even some symptoms of Parkinson’s.
The challenge now, says Kaptchuk, is to uncover the mechanisms behind
these physiological responses—what is happening in our bodies, in our
brains, in the method of placebo delivery (pill or needle, for
example), even in the room where placebo treatments are administered
(are the physical surroundings calming? is the doctor caring or curt?).
The placebo effect is actually many effects woven together—some
stronger than others—and that’s what Kaptchuk hopes his “pill versus
needle” study shows. The experiment, among the first to tease apart the
components of placebo response, shows that the methods of placebo
administration are as important as the administration itself, he
explains. It’s valuable insight for any caregiver: patients’
perceptions matter, and the ways physicians frame perceptions can have
significant effects on their patients’ health.
For the last 15 years, Kaptchuk and fellow researchers have been
dissecting placebo interventions—treatments that, prior to the 1990s,
had been studied largely as foils to “real” drugs. To prove amedicine
is effective, pharmaceutical companies must show not only that their
drug has the desired effects, but that the effects are significantly
greater than those of a placebo control group. Both groups often show
healing results, Kaptchuk explains, yet for years, “We were struggling
to increase drug effects while no one was trying to increase the
placebo effect.”
Last year, he and colleagues from several Harvard-affiliated hospitals
created the Program in Placebo Studies and the Therapeutic Encounter
(PiPS), headquartered at Beth Israel Deaconess Medical Center—the only
multidisciplinary institute dedicated solely to placebo study. It’s a
nod to changing attitudes in Western medicine, and a direct result of
the small but growing group of researchers like Kaptchuk who study not
if, but how, placebo effects work. Explanations for the phenomenon come
from fields across the scientific map—clinical science, psychology,
anthropology, biology, social economics, neuroscience. Disregarding the
knowledge that placebo treatments can affect certain ailments, Kaptchuk
says, “is like ignoring a huge chunk of healthcare.” As caregivers, “we
should be using every tool in the box.”
Western medicine, however, has been slow to agree with him—partly
because of his message, and in his case, often because of the
messenger. An acupuncturist by training, he is an unlikely leader in
the halls of academia. With a degree in Chinese medicine from an
institute in Macao, Kaptchuk is one of the few faculty members at
Harvard Medical School (HMS) with neither a Ph.D. nor M.D.—“a debit,
not a credit at most medical schools,” says Finland professor of
clinical pharmacology emeritus Peter Goldman, one of his early Harvard
advisers. (Kaptchuk’s diploma is recognized as a doctorate in many
states, but not in Massachusetts.) When Kaptchuk came to Harvard in
1995, “he knew about Chinese herbs and healing needles, and he’d
written a very fine book on Chinese medicine [The Web That Has No
Weaver (1983)],” says Goldman, “but he didn’t know the first thing
about how to conduct clinical studies.”
Kaptchuk joined the faculty as an instructor in medicine and
apprenticed himself to several seasoned clinicians and investigators.
Within a few years, he was winning National Institutes of Health grants
and publishing in medicine’s top journals. “What his colleagues saw was
a fierce intellect and curiosity,” said Goldman. “He was asking
questions no one was asking.”
Ironically, says Kaptchuk, it was his success as an acupuncturist that
made him leave the profession for academia. “Patients who came to me
got better,” he says, but sometimes their relief began even before he’d
started his treatments. He didn’t doubt the value of acupuncture, but
he suspected something else was at work. His hunch was that it was his
engagement with patients—and perhaps even the act of caring itself.
For his ideas to gain traction with Western doctors, however, Kaptchuk
knew he needed scientific proof. His chance would come in the early
2000s in a collaboration with gastroenterologists studying irritable
bowel syndrome (IBS), a chronic gastrointestinal disorder accompanied
by pain and constipation. The experiment split 262 adults with IBS into
three groups: a no-treatment control group, told they were on a waiting
list for treatment; a second group who received sham acupuncture
without much interaction with the practitioner; and a third group who
received sham acupuncture with great attention lavished upon them—at
least 20 minutes of what Kaptchuk describes as “very schmaltzy” care
(“I’m so glad to meet you”; “I know how difficult this is for you”;
“This treatment has excellent results”). Practitioners were also
required to touch the hands or shoulders of members of the third group
and spend at least 20 seconds lost in thoughtful silence.
The results were not surprising: the patients who experienced the
greatest relief were those who received the most care. But in an age of
rushed doctor’s visits and packed waiting rooms, it was the first study
to show a “dose-dependent response” for a placebo: the more care people
got—even if it was fake—the better they tended to fare.
Kaptchuk’s innovative studies were among the first to separate
components of the placebo effect, explains Applebaum professor of
medicine Russell Phillips, director of the Center for Primary Care at
HMS. For years, doctor-patient interactions were lumped into a generic
“placebo response”: a sum of such variables as patients’ reporting bias
(a conscious or unconscious desire to please the researchers); patients
simply responding to doctors’ attention; the different methods of
placebo delivery; and symptoms subsiding without treatment—the
inevitable trajectory of most chronic ailments. “There was simply no
way to quantify the ritual of medicine,” says Phillips of the
doctor-patient interaction. And the ritual, he adds, is the one finding
from placebo research that doctors can apply to their practice
immediately.
But other placebo treatments (sham acupuncture, pills, or other fake
interventions) are nowhere near ready for clinical application—and
Kaptchuk is not recommending that they should be. Such treatments all
require deception on the part of doctors, an aspect of placebo medicine
that raises serious ethical questions for practitioners.
This was disturbing for Kaptchuk, too; deception played no role in his
own success as a healer. But years of considering the question led him
to his next clinical experiment: What if he simply told people they
were taking placebos? The question ultimately inspired a pilot study,
published by the peer-reviewed science and medicine journal PLOS ONE in
2010, that yielded his most famous findings to date. His team again
compared two groups of IBS sufferers. One group received no treatment.
The other patients were told they’d be taking fake, inert drugs
(delivered in bottles labeled “placebo pills”) and told also that
placebos often have healing effects.
The study’s results shocked the investigators themselves: even patients
who knew they were taking placebos described real improvement,
reporting twice as much symptom relief as the no-treatment group.
That’s a difference so significant, says Kaptchuk, it’s comparable to
the improvement seen in trials for the best real IBS drugs.
Although this IBS “open-label” study was small and has yet to be
replicated, fellow placebo researcher Frank Miller of the department of
bioethics at the National Institutes of Health considers it a
significant step toward legitimizing placebo studies. But to really
change minds in mainstream medicine, Miller says, researchers have to
show biological evidence that minds actually change—a feat achieved
only in the last decade through imaging technology such as positron
emission tomography (PET) scans and functional magnetic resonance
imaging (fMRI).
The first evidence of a physiological basis for the placebo effect
appeared in the late 1970s, when researchers studying dental patients
found that by chemically blocking the release of endorphins—the brain’s
natural pain relievers—scientists could also block the placebo effect.
This suggested that placebo treatments spurred chemical responses in
the brain that are similar to those of active drugs, a theory borne out
two decades later by brain-scan technology. Researchers like
neuroscientist Fabrizio Benedetti at the University of Turin have since
shown that many neurotransmitters are at work—including chemicals that
use the same pathways as opium and marijuana. Studies by other
researchers have shown that placebos increase dopamine (a chemical that
affects emotions and sensations of pleasure and reward) in the brains
of Parkinson’s patients, and patients suffering from depression who’ve
been given placebos reveal changes in electrical and metabolic activity
in several different regions of the brain.
Kaptchuk’s team has investigated the neural mechanisms of placebos in
collaboration with the Martinos Center for Biomedical Imaging at
Massachusetts General Hospital. In two fMRI studies published in the
Journal of Neuroscience in 2006 and 2008, they showed that placebo
treatments affect the areas of the brain that modulate pain reception,
as do negative side effects from placebo treatment—“nocebo effects.”
(Nocebo is Latin for “I shall harm”; placebo means “I shall please.”)
But nocebo effects also activate the hippocampus, a different area
associated with memory and anxiety. As happened with Kaptchuk’s
patients in the “pill versus needle” study, the headaches, nausea,
insomnia, and fatigue that result from fake treatments can be painfully
real, afflicting about a quarter of those assigned to placebo treatment
in drug trials(see “The Nocebo Effect,” May-June 2005). “What we
‘placebo neuroscientists’…have learned [is] that therapeutic rituals
move a lot of molecules in the patients’ brain, and these molecules are
the very same as those activated by the drugs we give in routine
clinical practice,” Benedetti wrote in an e-mail. “In other words,
rituals and drugs use the very same biochemical pathways to influence
the patient’s brain.” It’s those advances in “hard science,” he added,
that have given placebo research a legitimacy it never enjoyed before.
This new visibility has encouraged not only research funds but also
interest from healthcare organizations and pharmaceutical companies. As
healthcare companies increasingly reward doctors for maintaining
patients’ health (rather than for the number of procedures they
perform), “research like Ted’s becomes increasingly relevant,” says
Minot professor of medicine and HMS dean for graduate education David
Golan, a professor of biological chemistry and molecular pharmacology.
This year, the Robert Wood Johnson Foundation, the nation’s largest
philanthropy focused on health and healthcare, awarded Kaptchuk’s PiPS
program a $250,000 grant to support a series of seminars at Harvard
designed to connect placebo experts with researchers in related fields.
And the latest findings to emerge from PiPS—a 2012 study showing that
genetic variations may explain why only certain people respond to
placebo effects—has caught the attention of the Food and Drug
Administration.
That study, published last Octoberin PLOS ONE, showed that patients
with a certain variation of a gene linked to the release of dopamine
were more likely to respond to sham acupuncture than patients with a
different variation—findings that could change the way pharmaceutical
companies conduct drug trials, says Gunther Winkler, principal of ASPB
Consulting, LLC, which advises biotech and pharmaceutical firms.
Companies spend millions of dollars and often decades testing drugs;
every drug must outperform placebos if it is to be marketed. “If we can
identify people who have a low predisposition for placebo response,
drug companies can preselect for them,” says Winkler. “This could
seriously reduce the size, cost, and duration of clinical
trials…bringing cheaper drugs to the market years earlier than before.”
Not all of Kaptchuk’s studies have been so warmly received. Though few
academics quarrel with the quality of his research, he’s remained a
prime target for such watchdog groups as Quackwatch and The Skeptics’
Society, organizations that question nonconventional medical
approaches. (Other well-known targets include Deepak Chopra, Andrew
Weil ’63, M.D. ’68, and the late Nobel Prize winner Linus Pauling.) In
2011, he and a team of researchers published a paper in The New England
Journal of Medicine (NEJM) that raised the hackles of some of his
fiercest critics.
That paper (praised by scholars as one of the most carefully controlled
and definitive placebo studies ever done) described a study of 40
asthma patients given four different interventions: active treatments
with real albuterol inhalers; placebo treatments with fake inhalers
that delivered no medication; sham acupuncture treatments; and
intervals with no treatment at all. The patients returned for 12
sequential visits, receiving each type of treatment three times—a novel
approach in placebo study that created a large amount of data (480
treatments in total) and turned subjects into their own controls (if
patients are compared to themselves from one treatment to the next,
researchers can eliminate subjects’ individual differences as a
variable). The researchers had hoped to find improved lung function
with both the real and sham treatments; what they found instead was
that only the real treatment yielded results—the others showed no
significant improvement. Yet when Kaptchuk’s team measured patients’
own assessments of improvement, the researchers found no difference
reported between the real and sham treatments: the patients’subjective
responses directly contradicted their own objective physical measures.
To Dr. Harriet Hall, a retired family physician who writes critically
about alternative and complementary medicine for such publications as
Skeptic Magazine and Skeptical Inquirer, this discrepancy between
objective and subjective results is precisely where the danger lies. As
she told a reporter for The Atlantic in December 2011, following the
publication of Kaptchuk’s NEJM study, “Asthma can be fatal. If the
patient’s lung function is getting worse but a placebo makes them feel
better, they might delay treatment until it is too late.”
To Kaptchuk’s team, on the other hand, the conflicting results not only
reveal important lessons for researchers and clinicians, but illuminate
a gap that is central to placebo research. “Placebos have limitations,
and we need to know what they are,” Kaptchuk says. “We’d hoped for
measurable objective changes in breathing; what we got instead was a
more precise diagram of placebo effects and how clearly the ritual of
medicine makes people more comfortable.” That in itself is important
information, he says. “Our job is to make people feel better,” and
though this study was small, “what we’ve really done here is open up a
new set of questions.” No one has yet studied how long-term experience
with the ritual of medicine might ultimately affect the course of
chronic afflictions, he says. “We hope we’ve opened up that path.”
Kaptchuk and his team have begun to take steps in that direction,
continuing to ask new questions and push the boundaries of placebo
research. A study published online this past year in the Proceedings of
the National Academy of Sciences demonstrated that the placebo response
can occur even at the unconscious level. The team showed that images
flashed on a screen for a fraction of a second—too quickly for
conscious recognition—could trigger the response,but only if patients
had learned earlier to associate those specific images with healing.
Thus, when patients enter a room containing medical equipment they
associate with the possibility of feeling better, “the mind may
automatically make associations that lead to actual positive health
outcomes,” says psychiatry research fellow Karin Jensen, the study’s
lead author.
Those findings led to the team’s most recent work: imaging the brains
of physicians whilethey treat patients—a side of the treatment equation
that no one had previously examined. (The researchers constructed an
elaborate set-up in which the doctors lay in fMRI machines specially
equipped to enable them both to see their patients outside the machine
and administer what they thought was a nerve-stimulating treatment.)
“Doctors give subtle cues to their patients that neither may be aware
of,” Kaptchuk explains. “They are a key ingredient in the ritual of
medicine.” The hope is that the new brain scans will reveal how
doctors’ unconscious thought figures into the treatment recipe.
Within academia, Kaptchuk and his fellow researchers have not escaped
criticism, but the voices have been few and far between. The most
notable appeared in 2001 in the NEJM—the same publication that included
Kaptchuk’s asthma study a decade later. In a paper titled, “Is the
Placebo Powerless?” two Danish researchers reviewed 114 published
studies involving 7,500 patients and questioned both the research
methods and the short duration of most placebo studies. Many of the
trials reviewed lacked “no-treatment” groups—an important control group
missing even in Kaptchuk’s first “pill versus needle” study.
But Kaptchuk’s response to such criticism is perhaps as rare in
academia as his pedigree. “If I remember correctly,” said Asbjorn
Hrobjartsson, the lead author of that 2001 paper during a recent phone
conversation, “Ted was already thinking along the same lines as we were
and realized [our paper] pointed out real methodological problems.”
When Hrobjartsson came to speak at Harvard a year later, he stayed at
Kaptchuk’s home, and in 2011, the two coauthored a paper (with the
NIH’s Frank Miller) on biases and best practices in placebo study.
When Kaptchuk talks about Hrobjartsson’s 2001 paper now, he winces,
then nods with acceptance. “At first when I read it, I worried I’d be
out of a job,” he says. “But frankly, [Hrobjartsson] was absolutely
right.” In order to legitimize his findings to mainstream
practitioners, the results must be expertly quantified, he
acknowledges. “We have to transform the art of medicine into the
science of care.”
Cara Feinberg is a journalist working in print and documentary
television. She can be reached through her website at
www.CaraFeinberg.com.
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