Placebo effeect

placebo effect

"The physician's belief in the treatment and the patient's faith in the physician exert a mutually reinforcing effect; the result is a powerful remedy that is almost guaranteed to produce an improvement and sometimes a cure." -- Petr Skrabanek and James McCormick, Follies and Fallacies in Medicine, p. 13.

The placebo effect is the measurable, observable, or felt improvement in health or behavior not attributable to a medication or treatment that has been administered.

A placebo (Latin for "I shall please") is a pharmacologically inert substance (such as saline solution or a starch tablet) that produces an effect similar to what would be expected of a pharmacologically active substance (such as an antibiotic).

By extension, "fake" surgery and "fake" therapies are considered placebos.

The idea of the placebo in modern times originated with H. K. Beecher. He evaluated 15 clinical trials concerned with different diseases and found that 35% of 1,082 patients were satisfactorily relieved by a placebo alone ("The Powerful Placebo," 1955). Other studies have since calculated the placebo effect as being even greater than Beecher claimed. For example, studies have shown that placebos are effective in 50 or 60 percent of subjects with certain conditions, e.g., "pain, depression, some heart ailments, gastric ulcers and other stomach complaints."* And, as effective as the new psychotropic drugs seem to be in the treatment of various brain disorders, some researchers maintain that there is not adequate evidence from studies to prove that the new drugs are more effective than placebos.

Beecher started a wave of studies aimed at understanding how something (improvement in health) could be produced by nothing (the inactive placebo). Unfortunately, many of the studies have not been of particularly high quality. In fact, it has been argued by Kienle and Kiene (1997) that, contrary to what Beecher claimed, a reanalysis of his data found "no evidence of any placebo effect in any of the studies cited by him." The reported improvements in heath were real but were due to other things that produced "false impressions of placebo effects." The reanalysis of Beecher's data claims that the improvements were due to:

Spontaneous improvement, fluctuation of symptoms, regression to the mean, additional treatment, conditional switching of placebo treatment, scaling bias, irrelevant response variables, answers of politeness, experimental subordination, conditioned answers, neurotic or psychotic misjudgment, psychosomatic phenomena, misquotation, etc.

What the reanalysis shows is that there are a number of factors that can affect many treatments and the evaluation of those treatments, making it very difficult to be sure just what it is about an intervention that produces improvement or perceived improvement. We must also consider "artifacts such as the natural history of a disease (that is, the tendency for people to get better or worse during the course of an illness irrespective of any treatment at all), the fact that people behave differently when they are participating in an experiment than when they are not, a desire to please the experimental staff by providing socially desirable answers..." (Bausell 2007: 27) and a host of other factors unrelated to the pill we are administering and independently of any mechanism that we believe is producing any observed effects.

In May 2001, The New England Journal of Medicine published an article that called into question the validity of the placebo effect. "Is the Placebo Powerless? An Analysis of Clinical Trials Comparing Placebo with No Treatment" by Danish researchers Asbjorn Hrobjartsson and Peter C. Gotzsche "found little evidence in general that placebos had powerful clinical effects." Their meta-analysis of 114 studies found that "compared with no treatment, placebo had no significant effect on binary outcomes, regardless of whether these outcomes were subjective or objective. For the trials with continuous outcomes, placebo had a beneficial effect, but the effect decreased with increasing sample size, indicating a possible bias related to the effects of small trials." (Most of the studies evaluated by Hrobjartsson and Gotzsche were small: for 82 of the studies the median size was 27 and for the other 32 studies the median was 51.)

"The high levels of placebo effect which have been repeatedly reported in many articles, in our mind are the result of flawed research methodology," said Dr. Hrobjartsson, professor of medical philosophy and research methodology at the University of Copenhagen.*

Typical of the kind of flawed research methodology Hrobjartsson is referring to would be that of surgeon J. Bruce Moseley who performed fake knee surgery on eight of ten patients. (Fake surgery involves making an incision on the knee and stitching it up.) Six months after the surgery all the patients were satisfied customers. Rather than conclude that the patients didn't need surgery or that the surgery was useless because in time the patients would have healed on their own, he and others concluded that the healing of the eight who did not have surgery was due to the placebo effect, while the two who had real surgery were better because of having had the operation. Irving Kirsch and Guy Sapirstein have been accused of making the same kind of methodological error in their controversial meta-analysis that found that anti-depressants work by the placebo effect, rather than that anti-depressants are unnecessary and useless.

One more example should suffice to make the point that better designs of placebo studies are needed.

Forty years ago, a young Seattle cardiologist named Leonard Cobb conducted a unique trial of a procedure then commonly used for angina, in which doctors made small incisions in the chest and tied knots in two arteries to try to increase blood flow to the heart. It was a popular technique—90 percent of patients reported that it helped—but when Cobb compared it with placebo surgery in which he made incisions but did not tie off the arteries, the sham operations proved just as successful. The procedure, known as internal mammary ligation, was soon abandoned ("The Placebo Prescription" by Margaret Talbot, New York Times Magazine, January 9, 2000).*

Did Cobb show that this kind of surgery works by the placebo effect? Or did he show that the surgery was unnecessary because most of the patients would have healed on their own if nothing had been done?

To rule out the natural history of a disease or regression to the mean, many researchers have use a third control group—those who receive no treatment at all. If the placebo group shows better results than the group getting nothing, then surely the placebo is effective. Hrobjartsson and Gotzsche think most of these studies, too, are flawed, mainly due to having samples that are too small or due to patients who make reports aimed at pleasing the researcher.

After the publication of the Hrobjartsson and Gotzsche study, Dr. John C. Bailar III said in an editorial that accompanied the study: "The shoe is on the other foot now. The people who claim there are placebo effects are going to have to show it." The need, he said, is for large, rigorously designed studies that clearly define and measure effects of drugs and therapies versus placebos versus no intervention at all. These studies will have to clearly distinguish objective measurements (such as blood pressure, cholesterol levels, etc.) and subjective measurements (such as reports of pain or evaluative sensory observations by researchers, e.g., "I can see your tumor is smaller" or "I can see you are not as depressed as before").

The kind of study called for by Dr. Bailar has been done and several such studies are reviewed in chapter nine of R. Barker Bausell's Snake Oil Science (2007): "How We Know That the Placebo Effect Exists." One in particular is worth reviewing here. It was published in the Journal Pain two months after the Hrobjartsson and Gotzsche article. "Response expectancies in placebo analgesia and their clinical relevance" was the work of Antonella Pollo et al. and demonstrated that placebos can help people with serious pain. The following is from their abstract:

Thoracotomized patients were treated with buprenorphine [a powerful pain reliever] on request for 3 consecutive days, together with a basal intravenous infusion of saline solution. However, the symbolic meaning of this basal infusion was changed in three different groups of patients. The first group was told nothing about any analgesic effect (natural history). The second group was told that the basal infusion was either a powerful painkiller or a placebo (classic double-blind administration). The third group was told that the basal infusion was a potent painkiller (deceptive administration). Therefore, whereas the analgesic treatment was exactly the same in the three groups, the verbal instructions about the basal infusion differed. The placebo effect of the saline basal infusion was measured by recording the doses of buprenorphine requested over the three-days treatment. We found that the double-blind group showed a reduction of buprenorphine requests compared to the natural history group. However, this reduction was even larger in the deceptive administration group. Overall, after 3 days of placebo infusion, the first group received 11.55 mg of buprenorphine, the second group 9.15 mg, and the third group 7.65 mg. Despite these dose differences, analgesia was the same in the three groups. These results indicate that different verbal instructions about certain and uncertain expectations of analgesia produce different placebo analgesic effects, which in turn trigger a dramatic change of behaviour leading to a significant reduction of opioid intake.

The patients who thought their IV contained a powerful pain reliever required 34% less of the analgesic than the patients who weren't told anything about their IV and 16% less than the patients who were told the IV could be either a powerful pain killer or a placebo. Each group got exactly the same amount of pain killer but their requests for the analgesic differed dramatically. The only significant difference among the three groups was the set of verbal instructions about the basal infusion. The study was too short for the differences to be explained by the natural history of recovery, regression, or any of the other alternatives found by Hrobjartsson and Gotzsche.

Several things are worth noting about this experiment. The setting involves treatment being provided by medical personnel in a medical facility. This kind of setting usually involves a strong desire for recovery or relief on the part of the patient, as well as a belief that the treatment will be effective. The different verbal instructions about the basal IV would lead to different expectations. Belief, motivation, and expectation are essential to the placebo effect. Classical conditioning and suggestion by an authoritative healer seem to be triggering mechanisms for the placebo effect (Bausell 2007: 131).

the psychological hypothesis: it's all in your mind

Some believe the placebo effect is purely psychological. Irving Kirsch, a psychologist at the University of Connecticut, believes that the effectiveness of Prozac and similar drugs may be attributed almost entirely to the placebo effect. He and Guy Sapirstein analyzed 19 clinical trials of antidepressants and concluded that the expectation of improvement, not adjustments in brain chemistry, accounted for 75 percent of the drugs' effectiveness (Kirsch 1998). "The critical factor," says Kirsch, "is our beliefs about what's going to happen to us. You don't have to rely on drugs to see profound transformation." In an earlier study, Sapirstein analyzed 39 studies, done between 1974 and 1995, of depressed patients treated with drugs, psychotherapy, or a combination of both. He found that 50 percent of the drug effect is due to the placebo response.

A person's beliefs and hopes about a treatment, combined with their suggestibility, may have a significant biochemical effect, however. Sensory experience and thoughts can affect neurochemistry. The body's neurochemical system affects and is affected by other biochemical systems, including the hormonal and immune systems. Thus, it is consistent with current knowledge that a person's hopeful attitude and beliefs may be very important to their physical well-being and recovery from injury or illness.

The psychological explanation seems to be the one most commonly believed. Perhaps this is why many people are dismayed when they are told that the effective drug they are taking is a placebo. This makes them think that their problem is "all in their mind" and that there is really nothing wrong with them. Yet, there are too many studies that have found objective improvements in health from placebos to support the notion that the placebo effect is entirely psychological.

Doctors in one study successfully eliminated warts by painting them with a brightly colored, inert dye and promising patients the warts would be gone when the color wore off. In a study of asthmatics, researchers found that they could produce dilation of the airways by simply telling people they were inhaling a bronchiodilator, even when they weren't. Patients suffering pain after wisdom-tooth extraction got just as much relief from a fake application of ultrasound as from a real one, so long as both patient and therapist thought the machine was on. Fifty-two percent of the colitis patients treated with placebo in 11 different trials reported feeling better -- and 50 percent of the inflamed intestines actually looked better when assessed with a sigmoidoscope ("The Placebo Prescription" by Margaret Talbot, New York Times Magazine, January 9, 2000).*

It is unlikely that such effects are purely psychological.

In fact, Martina Amanzio et al. (2001) demonstrated that "at least part of the physiological basis for the placebo effect is opioid in nature" (Bausell 2007: 160). We can be conditioned to release such chemical substances as endorphins, catecholamines, cortisol, and adrenaline. One reason, therefore, that people report pain relief from both acupuncture and sham acupuncture is that both are placebos that stimulate the opioid system.

the process-of-treatment belief

Another popular belief is that a process of treatment that involves showing attention, care, affection, etc., to the patient/subject, a process that is encouraging and hopeful, may itself trigger physical reactions in the body which promote healing. According to Dr. Walter A. Brown, a psychiatrist at Brown University,

there is certainly data that suggest that just being in the healing situation accomplishes something. Depressed patients who are merely put on a waiting list for treatment do not do as well as those given placebos. And—this is very telling, I think—when placebos are given for pain management, the course of pain relief follows what you would get with an active drug. The peak relief comes about an hour after it's administered, as it does with the real drug, and so on. If placebo analgesia was the equivalent of giving nothing, you'd expect a more random pattern ("The Placebo Prescription" by Margaret Talbot, New York Times Magazine, January 9, 2000).*

Dr. Brown and others believe that the placebo effect is mainly or purely physical and due to physical changes that promote healing or feeling better. So, what is the explanatory mechanism for the placebo effect? Some think it is the process of administering it. It is thought that the touching, the caring, the attention, and other interpersonal communication that is part of the controlled study process (or the therapeutic setting), along with the hopefulness and encouragement provided by the experimenter/healer, affect the mood, expectations, and beliefs of the subject, which in turn triggers physical changes such as release of endorphins, catecholamines, cortisol, or adrenaline. The process reduces stress by providing hope or reducing uncertainty about what treatment to take or what the outcome will be. The reduction in stress prevents or slows down further harmful physical changes from occurring. The healing situation provokes a conditioned response. The patient's been healed before by the doctor (or thinks she's been healed before by the doctor) and expects to be healed again.

the ethical dilemma

The power of the placebo effect has led to an ethical dilemma. One should not deceive other people, but one should relieve the pain and suffering of one's patients. Should one use deception to benefit one's patients? Is it unethical for a doctor to knowingly prescribe a placebo without informing the patient? If informing the patient reduces the effectiveness of the placebo, is some sort of deception warranted in order to benefit the patient? Some doctors think it is justified to use a placebo in those types of cases where a strong placebo effect has been shown and where distress is an aggravating factor.* Others think it is always wrong to deceive the patient and that informed consent requires that the patient be told that a treatment is a placebo treatment. Others, especially complementary and alternative medicine (CAM) practitioners, don't even want to know whether a treatment is a placebo or not. Their attitude is that as long as the treatment is effective, who cares if it a placebo?

While it may be unethical to knowingly package, prescribe, or sell placebos as magical cures, the CAM folks seem to think they are ethical because they really believe in their chi, meridians, yin, yang, prana, vata, pitta, kapha, auras, chakras, energies, spirits, succussion, natural herbs, water with precise and selective memory, subluxations, cranial and vertebral manipulations, douches, body maps, divinities, and various unobservable processes that allegedly carry out all sorts of magical analgesic and curative functions.

are placebos dangerous?

While skeptics may reject faith, prayer and "alternative" medical practices such as bioharmonics, chiropractic, and homeopathy, such practices may not be without their salutary effects. Clearly, they can't cure cancer or repair a punctured lung, and they might not even prolong life by giving hope and relieving distress as is sometimes thought. But administering placebo therapies does involve interacting with the patient in a caring, attentive way, and this can provide some measure of comfort. However, to those who say "what difference does it make why something works, as long as it seems to work" I reply that it is likely that there is something that works even better and might even be cheaper. Worse, some people might seek out a quack healer for a serious disorder that isn't affected by the quack therapy but could be relieved or cured by conventional medicine. Furthermore, placebos may not always be beneficial or harmless. John Dodes notes:

Patients can become dependent on nonscientific practitioners who employ placebo therapies. Such patients may be led to believe they're suffering from imagined "reactive" hypoglycemia, nonexistent allergies and yeast infections, dental filling amalgam "toxicity," or that they're under the power of qi or extraterrestrials. And patients can be led to believe that diseases are only amenable to a specific type of treatment from a specific practitioner (The Mysterious Placebo by John E. Dodes, Skeptical Inquirer, Jan/Feb 1997).

In other words, the placebo can be an open door to quackery. R. Barker Bausell speculates that since complementary and alternative medicine (CAM) practitioners' greatest asset is their nourishment of hope (2007: 294), "such therapies may be engendering nothing more than the expectation that they will reduce pain by elaborate explanations, promises, and ceremonies" (p. 149). Packaging placebos is big business and is likely to get even bigger. The only thing that could slow down CAM atavism would be the sudden appearance of horrible side effects issuing from treatments like aura cleansings or homeopathic douches.

I'd say that there's about as much chance of that happening as there is of John Edward or James Van Praagh announcing to an audience that a spirit is telling him that one of the paying customers is an axe murderer.

See also conditioning, confirmation bias, control study, communal reinforcement, magical thinking, nocebo, Occam's razor, post hoc fallacy, regressive fallacy, selective thinking, self-deception, subjective validation, testimonials, and wishful thinking.

http://www.skepdic.com/placebo.html