2017年6月11日 星期日

A radical new hypothesis in medicine: give patients drugs they know don’t work. You Can Have the Placebo Effect, Even If You Know It's a Placebo

Oxford University Scientific Society

A radical new hypothesis in medicine: give patients drugs they know don’t work

Why the placebo effect is weirder and potentially more useful than we imagined.



Patients taking placebos don't have to think they're getting real drugs to enjoy the placebo effect. A new study published in the journal PLoS reports on patients who had irritable bowel syndrome and were told they were being given a placebo as part of a novel experiment. They took pills from a big bottle clearly marked "placebo"—and got better, anyway. "In addition to the bogus medication, the volunteers were given a true story—the story of the placebo effect," Steve Silberman explains explains on the PLoS blog. "The combination of the story and a supportive clinical environment were enough to prevail over the knowledge that there was really nothing in the pills. People in the placebo arm of the trial got better—clinically, measurably, significantly better—on standard scales of symptom severity and overall quality of life. In fact, the volunteers in the placebo group experienced improvement comparable to patients taking a drug called alosetron, the standard of care for IBS." Scientists believe the remarkable findings are the result of the body's "powerful self-healing network," which can be activated by "nothing more or less than a belief that one is receiving effective treatment." And while placebos aren't going to replace pharmaceuticals any time soon, Silberman calls the development "good news to anyone but investors in Pfizer, Roche, and GlaxoSmithKline."
Read original story in PLoS | Thursday, Dec. 23, 2010

Meet the Ethical Placebo: A Story that Heals

Irving Kirsch, photo by Bo Tenberg
Irving Kirsch at the University of Hull, photo by Bo Tenberg
A provocative new study called “Placebos Without Deception,” published on PLoS One today, threatens to make humble sugar pills something they’ve rarely had a chance to be in the history of medicine: a respectable, ethically sound treatment for disease that has been vetted in controlled trials.
The word placebo is ancient, coming to us from the Latin for “I shall please.” As far back as the 14th Century, the term already had connotations of fakery, sleaze, and deception. For well-to-do Catholic families in Geoffrey Chaucer’s day, the custom at funerals was to offer a feast to the congregation after the mourners sang the Office for the Dead (which contains the phrase placebo Domino in regione vivorum, “I shall please the Lord in the land of the living”). The unintended effect of this largesse was to inspire distant relatives and former acquaintances of the departed to crawl out of the woodwork, weeping copiously while praising the deceased, then hastening to the buffet. By the time Chaucer wrote his Canterbury Tales, these macabre freeloaders had been christened “placebo singers.”
In modern medicine, placebos are associated with another form of deception — a kind that has long been thought essential for conducting randomized clinical trials of new drugs, the statistical rock upon which the global pharmaceutical industry was built. One group of volunteers in an RCT gets the novel medication; another group (the “control” group) gets pills or capsules that look identical to the allegedly active drug, but contain only an inert substance like milk sugar. These faux drugs are called placebos.
Inevitably, the health of some people in both groups improves, while the health of others grows worse. Symptoms of illness fluctuate for all sorts of reasons, including regression to the mean. Since the goal of an RCT, from Big Pharma’s perspective, is to demonstrate the effectiveness of a new drug, the return to robust health of a volunteer in the control group is considered a statistical distraction. If too many people in the trial get better after downing sugar pills, the real drug will look worse by comparison — sometimes fatally so for the purpose of earning approval from the Food and Drug Adminstration.
For a complex and somewhat mysterious set of reasons, it is becoming increasingly difficult for experimental drugs to prove their superiority to sugar pills in RCTs, which was the subject of an in-depth article I published in Wired called “The Placebo Problem,” recipient of this year’s Kavli/AAAS Science Journalism of the Year award for a magazine feature.
Only in recent years, however, has it become obvious that the abatement of symptoms in control-group volunteers — the so-called placebo effect — is worthy of study outside the context of drug trials, and is in fact profoundly good news to anyone but investors in Pfizer, Roche, and GlaxoSmithKline. The emerging field of placebo research has revealed that the body’s repertoire of resilience contains a powerful self-healing network that can help reduce pain and inflammation, lower the production of stress chemicals like cortisol, and even tame high blood pressure and the tremors of Parkinson’s disease.
Jumpstarting this network requires nothing more or less than a belief that one is receiving effective treatment — in the form of a pill, a capsule, talk therapy, injection, IV, or acupuncture needle. The activation of this self-healing network is what we really mean when we talk about the placebo effect. Though inert in themselves, placebos act as passwords between the domain of the mind and the domain of the body, enabling the expectation of healing to be translated into cascades of neurotransmitters and altered patterns of brain activity that engender health.
That’s all well and good, but what does it mean in the real world of people getting sick? You can hardly expect the American Medical Association to issue a wink and a nod to doctors, encouraging them to prescribe sugar pills for seriously disabling conditions like chronic depression and Parkinson’s disease. Meanwhile, more and more studies each year — by researchers like Fabrizio Benedetti at the University of Turin, author of a superb new book called The Patient’s Brain, and neuroscientist Tor Wager at the University of Colorado — demonstrate that the placebo effect might be potentially useful in treating a wide range of ills. Then why aren’t doctors supposed to use it?
The medical establishment’s ethical problem with placebo treatment boils down to the notion that for fake drugs to be effective, doctors must lie to their patients. It has been widely assumed that if a patient discovers that he or she is taking a placebo, the mind/body password will no longer unlock the network, and the magic pills will cease to do their job.
Now, however, a group of leading placebo researchers — including Irving Kirsch at the University of Hull in England (who I interview at length below) and Ted Kaptchuk at Harvard — has produced a little bombshell of a study that makes these assumptions obsolete. For “Placebos Without Deception,” the researchers tracked the health of 80 volunteers with irritable bowel syndrome for three weeks as half of them took placebos and the other half didn’t. A painful, chronic gastrointestinal condition, IBS is serious business. It’s one of the top ten reasons why people seek medical care worldwide, accounting for millions of dollars a year in health care expenditures and lost work-hours.
In a previous study published in the British Medical Journal in 2008, Kaptchuk and Kirsch demonstrated that placebo treatment can be highly effective for alleviating the symptoms of IBS. This time, however, instead of the trial being “blinded,” it was “open.” That is, the volunteers in the placebo group knew that they were getting only inert pills — which they were instructed to take religiously, twice a day. They were also informed that, just as Ivan Pavlov trained his dogs to drool at the sound of a bell, the body could be trained to activate its own built-in healing network by the act of swallowing a pill.
In other words, in addition to the bogus medication, the volunteers were given a true story — the story of the placebo effect. They also received the care and attention of clinicians, which have been found in many other studies to be crucial for eliciting placebo effects. The combination of the story and a supportive clinical environment were enough to prevail over the knowledge that there was really nothing in the pills. People in the placebo arm of the trial got better — clinically, measurably, significantly better — on standard scales of symptom severity and overall quality of life. In fact, the volunteers in the placebo group experienced improvement comparable to patients taking a drug called alosetron, the standard of care for IBS.
Meet the ethical placebo: a powerfully effective faux medication that meets all the standards of informed consent.
The study is hardly the last word on the subject, but more like one of the first. Its modest sample size and brief duration leave plenty of room for followup research. (What if “ethical” placebos wear off more quickly than deceptive ones? Does the fact that most of the volunteers in this study were women have any bearing on the outcome? Were any of the volunteers skeptical that the placebo effect is real, and did that affect their response to treatment?) Before some eager editor out there composes a tweet-baiting headline suggesting that placebos are about to drive Big Pharma out of business, he or she should appreciate the fact that the advent of AMA-approved placebo treatments would open numerous cans of fascinatingly tangled worms. For example, since the precise nature of placebo effects is shaped largely by patients’ expectations, would the advertised potency and side effects of theoretical products like Placebex and Therastim be subject to change by Internet rumors, requiring perpetual updating?
100% pure placebo
Even at this preliminary stage in the research, however, it’s clear that it’s time to flip our ideas about fake pills upside down. It’s common to use the word “placebo” as a synonym for “scam.” Economists talk about placebo solutions to our economic catastrophe (tax cuts for the rich, anyone?). Online skeptics mock the billion-dollar herbal-medicine industry by calling it Big Placebo. The fact that our brains and bodies respond vigorously to placebos given in warm and supportive clinical environments, however, turns out to be very real.
We’re also discovering that the power of narrative is embedded deeply in our physiology. Perhaps that’s not surprising. In the long centuries before doctors discovered antibiotics, they often had little else but an observant eye, a listening ear, and a bag of nostrums with names like decoction of barley and compound infusion of roses to offer their desperately ill patients.
In an age of computerized diagnostics, talking about the power of storytelling in health care seems like a throwback to those medical Dark Ages. After reading the new study, however, one of the pioneers of placebo research, anthropologist Dan Moerman at the University of Michigan, noted how much even the volunteers who didn’t get placebos benefited from the support and attention of clinicians.
“I was really surprised at how well the non-placebo group did,” Moerman says in email. “Note I don’t call them a ‘no treatment group’ because they, and everyone else, received exemplary treatment here: they were listened to, examined, encouraged, supported. They were able to talk with, and be taken seriously by, people who understood their issues, things they probably had serious difficulty discussing with their own families. I think it likely that the effectiveness of the placebos above and beyond all the other treatment would have been diminished without the whole system of compassionate care.”
At the same time, as Kirsch explains in our interview, the volunteers who took placebos felt significantly better than those who didn’t. The act of taking the pills made a difference.
Placebo expert Amir Raz at McGill University observes that the new study follows up on a groundbreaking experiment conducted in 1964 by Lee Park and Uno Covi, who administered “open” placebos to 15 patients from a psychiatric clinic and tracked similar levels of improvement in their anxiety. In a paper slated to be published in the April 2011 issue of the Canadian Journal of Psychiatry, Raz will talk to many physicians who doubt that one has to lie to patients for placebos to be effective. In fact, in the real world of doctoring, many physicians prescribe medications at dosages too low to have an effect on their own, hoping to tap into the body’s own healing resources — though this is mostly acknowledged only in whispers, as a kind of trade secret.
Kirsch’s 2010 book The Emperor’s New Drugs caused a huge stir by claiming that the effectiveness of antidepressants — one of the top-selling classes of drugs in the world — may be entirely dependent on the placebo effect. Before spending time with him at a placebo workshop hosted at McGill in July, I was frankly expecting to meet a fiery anti-pharma avenger – albeit one with a compelling argument backed up by data.
Instead, Kirsch is a soft-spoken, modest, diligent, boyishly handsome 67-year-old psychologist who thoroughly understands why his notions are so upsetting to people who insist that their lives have been turned around by Paxil or Lexapro. He also has an intriguing personal history that includes organizing against the Vietnam War with Bertrand Russell, producing a Grammy-nominated comedy album in 1973 with the editors of National Lampoon, and playing violin in the Toledo Symphony behind Aretha Franklin. Kirsch is currently working on a new book about the potential of placebo therapy.
Silberman: What’s the most subversive aspect of this new study?
Kirsch: Simply that placebos work even when you tell people that they’re placebos. To me that’s fascinating. As is the fact that patients can experience substantial and clinically meaningful improvement of the symptoms of irritable bowel syndrome when given placebos.
One of the assumptions that we made in this study, however, is that you have to offer the patients a convincing rationale to use placebos as well as giving them a pill. That’s the next thing we have to test.
Silberman: What kinds of ailments are amenable to placebo treatment?
Kirsch: Depression, anxiety disorders, and pain; pain in particular is highly responsive to placebo therapy. Irritable bowel syndrome — we’ve shown that not only in this study, but in one published in the British Medical Journal a couple of years ago. Parkinson’s Disease, ulcers, and asthma too. There’s a long list of conditions treatable with placebos that have some subjective component and can be intensified by conditions like stress.
Silberman: If all of these ailments have a subjective component, does that mean they share a set of neurological mechanisms?
Kirsch: I’m afraid that’s outside my area of expertise. But I know what these conditions don’t share in common. The kinds of effects you see in the brain when people respond to a placebo depends on the condition you’re supposed to be treating. So if you take a placebo analgesic, you get reductions in activity in the brain’s pain matrix. If you take a placebo antidepressant, you get changes in brain activity in areas related to depression.
Silberman: Does the placebo response tell us anything about how active medicines work?
Kirsch: For any condition susceptible to placebos, the placebo effect is a component of the response to active medication. In most cases, placebo effects and drug effects are additive — the net response to the medication is larger because of placebo effects than it would be on its own.
Silberman: You’ve done a lot of work analyzing placebo effects in antidepressant therapy, which you write about in your book The Emperor’s New Drugs. Has your opinion of antidepressants evolved at all?
Kirsch: The more I learn, the more convinced I become that the benefits of drugs for depression are not biologically driven, but driven by the placebo effect. The thing that convinces me most is that nearly all drugs for depression — despite having very different chemical compositions — are of equal benefit. In other words, you have drugs that are completely different in what they do chemically — even drugs that operate by opposing mechanisms — creating the same level of effect.
The most commonly employed antidepressants are supposed to increase the amount of serotonin in synapses in the brain, but there are also antidepressants that decrease the level of serotonin in the brain, and they both have the same effect therapeutically. The effects of these drugs seem to be completely independent of their chemical composition.
Silberman: Dan Moerman mentioned to me in an email that he was surprised by how well the non-placebo group did in your study.
Kirsch: That’s true. We said that we compared open label placebo to a no-treatment control group, but actually, the ”no-treatment” description is not entirely accurate in this case. The patients in the control group met with the clinician before being given the pills and midway between the beginning and end of the study. Both visits were in the context of a warm, supportive, patient-practitioner relationship. Like many other researchers, we assume that the therapeutic relationship is an important component of the placebo effect.
But many people — including doctors — think that the therapeutic relationship entirely accounts for the placebo effect. Our data show that this is not true. If the placebo effect was entirely due to the therapeutic relationship — the time, attention, warmth, and enthusiasm communicated by the doctor — then our placebo pill would not have produced any effect beyond that seen in our “no-treatment” control condition, because the no-treatment control patients received the same level of therapeutic relationship as that received by patients in the placebo pill condition. That tells us two things –one, that giving patients the placebo pill improved their condition, and two, that the difference in improvement was due to getting the pill. It was not due to the therapeutic relationship.
Silberman: One of the ways that you prepped the volunteers in this trial was that you informed them that placebo effects work via conditioning, like Pavlov’s dogs being trained to salivate at the sound of a bell. What trains people all over the world to respond to act of taking a pill?
Kirsch: The existence of successful treatments. People come to expect and believe that they’re going to get better if they take medication. The whole process of going to a physician and being treated reinforces this belief. That constitutes the basic aspects of classical conditioning. Eventually, the pill alone is enough to produce a placebo effect, whether it contains an active drug or not.
Silberman: Does direct-to-consumer advertising also play a role? In America, when you open a magazine, the good-looking jock playing with puppies in the sun is the formerly depressed patient on Zoloft.
Navigating the road ahead with Abilify
Advertisement for Abilify, used to treat depression, schizophrenia, bipolar disorder, and autism-related irritability
Kirsch: No doubt about it. One thing that’s clear is that the placebo effect of antidepressants has gotten stronger over the years as these drugs have been more widely accepted, touted, and advertised. The response to them in general has increased because of the additivity I was talking about before.
Silberman: What would a world in which placebos were given openly by doctors look like?
Kirsch: Our study points to something that a number of people have suspected, but has been hard to demonstrate under controlled conditions: We have the capacity for healing physical conditions through psychological means. First, we have to accept that. Studies of placebo effects are great demonstrations of it.
You might think of this healing capacity as a self-regulatory mechanism. Then the question then becomes how best to unlock it. This kind of research shows the potential of our being able to treat certain conditions without drugs — particularly in cases where we don’t have effective drugs, and/or where the drugs we have are not much more effective than what we can accomplish with placebos. And especially in cases where the drugs carry serious risks.
Silberman: A lot of very smart people dismiss homeopathy, acupuncture, and other alternate treatments as nothing more than quackery for dullards — “woo,” as P.Z. Myers or Ben Goldacre might put it. But couldn’t the placebo response play the role of being, in a sense, the “active principle” of woo? For example, I recently saw a controlled trial of homeopathic therapy for rheumatoid arthritis that concluded that the effectiveness of the therapy was due to the homeopathic consultation process, not the little pills themselves. Your colleague Ted Kaptchuk spoke to me for my Wired article about the importance of “therapeutic ritual” in eliciting the placebo response, and homeopathic consultation — even if the notion that pills containing a few molecules at most of an active ingredient seems obviously ridiculous — is a good example of an elaborate therapeutic ritual. I think the door is still open on whether acupuncture does more than jump-start the placebo response…
Map of Acupuncture Meridians
Traditional map of 经络, the acupuncture meridians
Kirsch: That door is closing. I think the effects of acupuncture are largely placebo effects, if not entirely. It’s a very good placebo effect; a really healthy and large placebo effect. The last study we did on IBS was with placebo acupuncture — sham acupuncture. Sham acupuncture does as much good as real acupuncture. You can do it without needles and still get the same effect. Practitioners of acupuncture, homeopathy, and other alternative and complimentary medicines do an excellent job of eliciting and bolstering placebo effects.
We know from our research the things that make a difference: how much time you spend with a patient, how supportive and empathic you are, how well you listen, and how confident you are in being able to help. Complimentary and alternative medicine practitioners are particularly good at these things. These are obviously things that physicians can do as well, and some are very good at eliciting placebo effects.
But those qualities are becoming more rare in conventional medical practice. Certainly here in the UK, it’s very uncommon to have a good placebo intervention in primary care, because the standard visit with the doctor is ten minutes at most.
Silberman: Ten minutes sounds long to me. If I see my doctor for three minutes as she rushes around, it’s a good day.
Kirsch: In the IBS study we did in 2008, we maximized the amount of time spent in the initial interview, and other qualities of listening and empathy, and got much more substantial placebo effects.
Silberman: These days, however, the emphasis is increasingly on data-driven medicine — blood tests, genome and proteome scans, and the search for biomarkers. Studies like this suggest that narrative medicine as it was practiced in the 19th century — the doctor listening to the patient, hearing the story of the symptoms, and reframing it as a story of how the patient will get better — also plays a crucial role in healing.
Kirsch: We’re breaking the boundary between the two approaches. The reason we do studies like this is to make placebo research data-driven. We’re starting to build up a database on the effects of enhancing patient-physician contact, and on the administration of placebos openly and honestly, without deception.
Silberman: Have you had any hostile responses to your book from people who worry that by telling depressed people that antidepressants are really placebos, the pills will stop working?
Photo of Irving Kirsch by Bo Tenberg
Photo of Irving Kirsch by Bo Tenberg
Kirsch: Definitely. People have suggested that I take a line comparable to “don’t ask, don’t tell.” They say, “OK, so the placebo effect is doing most or all of the work. We don’t want to ruin that. We have nothing else to give our patients!” Well, now we know that the placebo effect still works even when people know they’re taking placebos. That’s one of the nice things we’ve learned from this study. Plus, there’s an ethical problem when you keep secret the fact that you’re giving someone a drug that barely works — especially when the drug has harmful effects as well.
Silberman: Has your research changed the way you think about taking medicine?
Kirsch: Interesting question. It has made me more wary. It certainly makes me less likely to talk to my doctor about getting an antidepressant if I’m feeling down or sad.
Silberman: What kinds of follow-up studies are needed now?
Kirsch: We know that open placebo treatment works for IBS. Does it also work for depression? How crucial is telling patients about the placebo effect? Might placebo therapy work even without giving patients a convincing rationale? My guess would be that it wouldn’t, but I don’t really know for sure.
Silberman: One interesting aspect of this study is that it suggests that are two layers of belief in the brain — one that knows there’s nothing in this pill, and another that knows that a placebo can be an effective treatment. It’s as if the brain can entertain two different notions of the effectiveness of a pill at once.
Kirsch: Yes, but they’re not contradictory notions. I believe in both. I know that this pill does not contain a physically active ingredient, and I also understand the conditioning process. I know that the placebo effect is real, so I understand that this inert pill might help trigger that healing response within me. We need to recognize and understand that patients are active agents in their treatment, not passive. The placebo effect does not come from the pill. It comes from the patient.