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Placebos in clinical practice

jontilburtBy Christopher Guadagnino, Ph.D.

A recent study reveals that physicians prescribe placebo treatments in clinical practice on a regular basis – a practice that on its face appears to violate professional ethics and raises questions about how and why placebos are being used, the propriety of their use, and the very way in which “placebo effect” ought to be conceptualized.

Placebos are traditionally understood as inert substances used in blinded clinical trials – dummy pills or saline injections administered to establish efficacy baselines for biomedically active therapies. Within that context, and used with a subject’s informed consent, placebos are viewed as ethical and necessary tools to filter out “noise” effects that accompany treatment outcomes. Prescribing them to patients in clinical encounters, however, conjures images of paternalistic manipulation to deceive or mollify difficult patients. The American Medical Association (AMA) two years ago issued policy guidance shunning such ethical transgressions.

But a study published in BMJ this October offers intriguing details about how physicians prescribe placebo treatments in clinical practice. They rarely prescribe traditionally-conceived inert placebos, but they regularly prescribe “active” substances – such as vitamins, over-the-counter analgesics, sedatives and antibiotics – even when there is no scientific evidence that those treatments will have specific biological impact on the patient’s condition at hand. In those situations, physicians anticipate therapeutic benefits deriving more from positive patient expectations than from the physiological mechanism of the treatment itself – which researchers deemed to be the defining feature of placebo, whether active or inert.

Reframing the placebo effect as clinicians’ ability to promote positive therapeutic expectations in patients, irrespective of the treatment prescribed, dramatically changes the meaning of the term. No longer viewed as noise or manipulation, the reframed conception of placebo treatment offers physicians a multitude of non-deceptive means to promote positive placebo responses – which manifest themselves as genuine symptomatic improvement. The power of patient expectation significantly impacts illness symptoms – a phenomenon that for decades has been demonstrated in studies involving both inert substances and pharmacologically active treatments. Therapeutic expectations can even produce an opposite “nocebo effect” – in which patients in clinical trials who are warned by physicians about a medication’s side effects report experiencing those negative effects even from inert placebo substances.

Some researchers believe that the placebo effect – understood as promoting positive therapeutic expectations in patients – is an essential dimension of the care process that physicians have a duty to harness in every clinical encounter with patients, whether prescribing inert or therapeutically active treatments. Doing so recaptures the art of medicine – fostering an empathetic healing relationship which leverages the power of the psycho-social state of the patient – a relationship they say is often sacrificed in the economically-driven paradigm of modern medicine, manifested in the 15-minute office visit.

Ethical and practical questions about placebo use remain. Research suggests that physicians might not be fully transparent with their patients about the use of placebos and might have mixed motivations for recommending such treatments, ranging from mollification of difficult patients, to genuine desire to try something that might improve a patient’s symptoms, accompanied by open discussion about the treatment’s potential therapeutic power despite the absence of scientific evidence.

It remains unknown the extent to which such disclosure may dilute the placebo effect, although some researchers believe the expectations created during the overall patient-physician encounter are the more important determinants of a placebo effect. Studies have been conducted, for example, demonstrating that morphine is more effective for pain relief when the patient sees it being administered by a clinician, rather than surreptitiously – suggesting that positive expectation itself is a key driver of the placebo response. Full disclosure of a placebo’s nature, in the context of empathetic and positive rapport, may be sufficient to harness the placebo effect, e.g., a statement such as: “This is a medicine not typically used for your condition, and there is no scientific literature to suggest that it will have a biological effect, but we could try it and it might benefit you.”

Placebo Prescribing Patterns

The recent BMJ study suggests that prescribing placebo treatments is a common practice among physicians. The study used a national survey of practicing internists and rheumatologists (679 of whom responded) – a group of physicians who commonly treat patients with debilitating chronic clinical conditions that are notoriously difficult to manage. The study defined placebo as “a treatment whose benefits (in the opinion of the clinician) derive from positive patient expectations and not from the physiological mechanism of the treatment itself,” and found that over half of respondents (55 percent) indicated they had recommended at least one placebo treatment within the previous year, while most said they believed that recommending such treatments is ethically permissible. Those findings were consistent across age, sex, race, specialty, practice setting and region, and are consistent with another recent study of physician placebo prescribing habits, published in the Journal of General Internal Medicine (JGIM) in January, which surveyed 231 academic physicians in the Chicago area and found that 45 percent had used placebo treatments in clinical practice, while eight percent indicated using placebo treatment more than 10 times in the past year.

The majority of physicians in the JGIM study believed that placebos have therapeutic effects – whether psychological or both psychological and physiological – and indicated a variety of types of health problems that they believed could benefit from placebo interventions: pain, mental or emotional disorders, gastrointestinal disorders, sexual dysfunction, recovery from drug addiction, neurological disorders, immune problems or allergies, cancer, cardiovascular disorders, and viral infections.

In the BMJ survey study, physiologically “active” treatments were more commonly reported by those who prescribed placebos (i.e., in which the clinician-perceived benefits derive from positive patient expectations and not from the physiological mechanism of the treatment itself), including over-the-counter analgesics (41 percent), vitamins (38 percent), antibiotics (13 percent), and sedatives (13 percent). Only two percent reported using “sugar pills,” and three percent using saline, as placebo treatments.

The study found that physicians might not be fully transparent with their patients about the use of placebos. Among those who did prescribe them, 68 percent said they usually describe placebo treatments as “a medicine not typically used for your condition but might benefit you,” while 18 percent introduced placebo treatments as “a medicine,” and nine percent said they typically describe placebo treatments as “a medicine with no known effects for your condition,” and only five percent reported typically describing the treatment as “a placebo.”

The researchers did not explore physicians’ motivations behind placebo prescribing, nor did they probe the ethical implications of their findings, although they did acknowledge that prescribing antibiotics and sedatives when they are not medically indicated could have adverse consequences for both patients and public health. The authors speculated that so few physicians recommend inert placebo treatments because it may no longer be possible for physicians to write a prescription for a sugar or bread pill, or physicians might have understandable reservations about recommending them, fearing these treatments are inherently deceptive and are not amenable to contemporary standards of informed consent.

They further speculate that physicians might have multiple, possibly conflicting, beliefs and motivations for recommending active placebo treatments: they might believe that a given benign and safe treatment might have some chance of working pharmacologically, despite remaining unproved for the symptoms or condition at hand; or that such treatments might promote positive expectations in patients or help the patient to feel like they are being taken care of.

The study’s lead author, Jon C. Tilburt, M.D., assistant professor of internal medicine and biomedical ethics at the Mayo Clinic, says that in debriefs with a few physicians after the survey, some physicians described prescribing active placebos as “therapeutic latitude” to administer “something that might work” and that might give patients some psychological benefit in the absence of other proved effective treatments for chronic symptomatic conditions.

Debriefed physicians also said they worried about the toxicity of pharmacologic alternatives to their placebo therapies, that they found it frustrating treating chronic symptoms, and that they were desperate to “do something” – which in contemporary medicine means prescribe a pill, notes Tilburt, who says he plans to conduct more qualitative research on physicians’ attitudes toward placebo prescribing.

Tilburt believes that there are many situations in which physicians try therapies without knowledge of whether or how they will work. He gives the example of a patient with hot flashes, dizziness and burning sensation in the legs. After careful medical workup, Tilburt says, a physician may have no definitive explanation or label for the patient’s condition. “I believe he has overly sensitive sensory nerves, so in consultation with a neurologist, and open conversation with the patient, I prescribe medication for neuropathy – which is painful nerve damage – even though there is no objective evidence of neuropathy. I trysomething, with benevolent intent. I take the patient’s experience as real data, even without objective physiological evidence,” says Tilburt. “That is not far removed from giving an active placebo,” he adds.

Explaining the Placebo Effect

Tilburt’s study was supported in part by the National Institutes of Health’s (NIH) Department of Bioethics, of which he was formerly a staff scientist. The NIH maintains that placebo effects often enhance the benefits of therapeutic interventions in clinical practice, and is sponsoring ongoing research into the psycho-social factors in the physician-patient relationship that promote hope and positive expectancy in patients; tools to elicit and maximize the placebo effect; specificity, timing and size of placebo effects; and ethical questions of placebo use.

In 2000, the NIH hosted a conference to develop an interdisciplinary research agenda on the science and ethics of the placebo, based on a scholarly assessment of the field. The following year it released a guide, The Placebo Effect in Clinical Practice, defining placebo effects as the positive physiological or psychological changes associated with the use – not only of inert medications or sham procedures – but also active substances or real procedures that produce unexpected beneficial effects, for example, antibiotics when prescribed for viral respiratory illnesses that are not expected to respond to antibiotic action.

The NIH views the placebo effect as a subset of a larger group of mind-brain-body effects such as the psycho-physiological effects of religious beliefs and devotional practices, meditation, faith-based healing, hypnosis and cultural effects. These mind-brain-body effects, according to the NIH, have been scientifically documented by an increasing body of research, but are not fully appreciated in contemporary medicine, in part as a legacy of the Cartesian model that envisions the mind as being something discrete from brain and body, and by the reductionist biomedical model of conventional medicine in which health care practitioners are trained to focus primarily on finding and eliminating physiologically demonstrable pathology.

The pejorative connotation of the term “placebo” – first coined in the early 19th century to describe a medicine adapted more to please than benefit the patient – persists, and is still typically associated with the randomized double-blind placebo-controlled clinical trial that allows investigators to subtract the “noise” of placebo effects from the actual therapeutic responses to newly developed drugs and medical/surgical procedures, notes the NIH guide. Medicine regularly included placebos as part of clinical practice before the rapid advances in medical/surgical techniques and proliferation of contemporary drugs in the second half of the last century, the guide notes. “Now we are witnessing a further evolution in how placebo and other related effects are perceived, facilitated by a substantial body of research that provides compelling evidence of mind-brain-body interactions at the organismal, cellular, and molecular levels,” including the biology of social interactions, the neurobiology of emotions, and molecular neuroendocrine and neural factors in inflammatory and infectious disease, the NIH adds.

Researchers at the NIH conference suggested that placebo effects operate through psycho-social mechanisms such as belief, conditioning, expectancy and meaning response – mechanisms that in turn evoke physiological responses that may affect biological pathways in neurological, immune, endocrine, cardiovascular, gastrointestinal and other organ systems to relieve disease symptoms.

Further understanding of the placebo effect also has important implications for clinical trials, the NIH guide notes, particularly the need to distinguish placebo effects from other potentially confounding factors that are sometimes grouped inappropriately with placebo effects – such as the natural history of the disease, investigator and patient biases, the reliability of measurements taken, regression to the mean, spontaneous remissions, and confounded therapeutic procedures. Complicating things further, the NIH adds, the relationship between placebo and treatment effects may not be purely additive, but rather dynamically interactive.

The National Center for Complementary and Alternative Medicine (NCCAM) has fashioned part of its research agenda around NIH’s placebo research goals, and is sponsoring studies to determine which aspects of the physician-patient interaction optimize positive therapeutic expectations, studies examining patient characteristics that may influence those expectations, and studies of brain imaging to examine the basic biology of placebo analgesia – including biological responses such as the release or endogenous opioids, according to NCCAM Director Josephine P. Briggs, M.D. “There is some evidence that expectancy and memory of pain relief activates the same receptors through which morphine acts, and this kind of research helps us understand the mechanisms our brain uses,” she says.

The general trend in placebo research is that patient belief impacts the efficacy of a placebo, so a quandary the medical profession has to deal with is how to combine full disclosure with education and reassurance in a way that does not undermine the placebo effect, says Briggs.

“It is clear that physicians not infrequently prescribe a medication without a strong expectation that it will treat a patient’s condition, but that it might have nonspecific effects, including reassurance and expectancy of improvement,” notes Briggs. physician may feel pressured to prescribe a placebo treatment, when his or her reassurance and time spent with a patient may be all that is needed,” she adds.

The “active” ingredient responsible for the placebo effect does not lie in the placebo itself, but rather in the meaning that patients project onto it, and the ability of sick people to respond powerfully and positively to meaningful clinical interactions is unavoidable, potentially potent, and to some extent controllable by the physician, according to placebo researcher Daniel E. Moerman, Ph.D., professor emeritus of anthropology, University of Michigan-Dearborn.

Most elements of medicine are meaningful to patients even if practitioners do not intend them to be so, such as the physician’s white coat and stethoscope, manner, enthusiasm and language; so the issue is less one of deception than of knowledge, says Moerman, noting examples in clinical studies:

  • Hospitalized surgical patients report more pain relief when given analgesics visibly by a clinician than when they are given hidden infusions of the same analgesics via intravenous line.
  • Both inert placebos and aspirin work better when labeled with a widely advertised brand.
  • Four inert placebo tablets a day have more effect than two a day.
  • Injections of inert placebo are more effective than oral placebo.
  • Active implanted pacemakers achieve marginally better results than inactive ones – both leading to substantial improvements.
  • Old drugs become less effective when new ones come along – more likely due to attitudes of physicians than to changes in human physiology.

Disclosing to a patient that the efficacy of a given treatment is unknown may not fatally undercut the positive effects of patient expectation. While blinded clinical trials demonstrate meaningful benefits of inert placebo treatments, a fair percent of patients in some trials who correctly identify that they have taken the placebo still report some benefit, notes Clarence H. Braddock III, M.D., MPH, a member of the American College of Physician’s Ethics, Professionalism and Human Rights Committee. “Ethically, even if you lose some benefit from disclosure, that is offset by candor and an enhanced relationship,” Braddock believes.

Moerman cites an open placebo trial several years ago at Johns Hopkins, in which psychiatric patients showed dramatic improvement even when they were told they were receiving a sugar pill during their treatment workup. Some of the patients, says Moerman, thought they were being lied to – they felt so much better that they thought they must have been given real medicine and not a sugar pill – while others articulated that they were responsible for their own improvement.

Ethical Boundaries

Disclosure remains a key issue in the clinical use of placebos. It is unethical for a physician to use a placebo in clinical practice unless the patient is informed and agrees to its use, according to a 2006 report by the AMA’s Council on Ethical and Judicial Affairs, which is now part of the AMA’s Code of Medical Ethics. The report defines placebo as a substance that the physician believes has no specific pharmacological effect upon the condition being treated – analogous to the definition used in Tilburt’s study – and advises physicians that they may utilize placebos in clinical practice to determine a diagnosis or appropriate treatment in the face of clinical uncertainty.

Another ethically acceptable scenario of placebo prescribing in clinical practice mirrors aspects of a blinded placebo-controlled clinical trial, known as an “N-of-1” trial, in which the physician and patient agree to experiment with two sets of pills, one real and one placebo. The patient takes one type of pill for a certain interval, then the other for another interval, and keeps track of symptoms. According to AMA policy, the physician need neither identify the placebo nor seek specific consent at the time of its administration, having secured the patients informed consent beforehand. The physician respects the patient’s autonomy and fosters a trusting relationship, while the patient still may benefit from the placebo effect.

The AMA warns that using placebos without the patient’s knowledge may undermine trust, compromise the patient-physician relationship and result in medical harm to the patient; and it says a placebo must not be given merely to mollify a difficult patient because doing so serves the convenience of the physician more than it promotes the patient’s welfare.

“The basis of our policy is for the patient to be as well-informed as possible,” according to AMA board member Ardis D. Hoven, M.D. In the absence of other proven treatment options, whether a physician prescribes an inert substance or active agent, Hoven says “you have to disclose what you know about the treatment. Absent that, it is a disservice to the patient.”

A physician’s intent is a factor in judging the ethics of placebo therapy. As long as the physician believes there may be a chance of pharmacologic benefit and is candid with the patient about what is known about a given drug, then the encounter passes muster, says Hoven. Drugs that are contraindicated or that carry possible adverse effects are outside ethical boundaries, she adds. As an infectious disease specialist, Hoven says it is bad medicine to prescribe an antibiotic for a viral infection – a drug she says is not going to be medically responsive – and she does not regard that as ethical placebo treatment.

Tilburt agrees that a physician’s motivation is an important component of placebo ethics. “Physicians are stuck, therapeutically, searching for ways to treat chronic refractory conditions. If we think that prescribing placebos is a shortcut to promoting a more healing relationship, it will instead undermine trust in the relationship,” he cautions. Just because a patient has intractable symptoms is not a sufficient reason to prescribe an unproved therapy; there has to be some reason to think it may have some benefit, Tilburt says. That means sometimes asking patients to endure their symptoms, he adds.

That inert placebos appear to be seldom used in clinical practice entails an irony, says Tilburt: “The good news is that not many physicians are actively deceiving patients with inert placebos. But if the impulse to heal means prescribing pills, and physicians are left with giving pharmacologically active pills, there is a risk of harming the patient. Whatever benefit we may have gained in eliminating deception we may have lost in exposing patients to risk.” Physicians must weigh the risk-benefit ratio of prescribing active placebos, cautions Tilburt, noting that drugs get pushed into the marketplace so rapidly, and that (according to a research study currently in press) one-third to one-half of physicians don’t actually know the FDA indications for certain drugs they prescribe, making it difficult in some cases to have an informed conversation with patients.

Hoven concedes that these issues are in “ethically gray” territory, and says decisions need to be made on a case-by-case basis. “Physicians want to make patients feel better. If it won’t harm the patient and there is no science that it will work – but the physician believes that there is a slight chance it might help – that’s probably okay, as long as the patient is part of the decision-making process,” says Hoven. “If a patient knows it’s a placebo and agrees to take it, it’s probably okay, even if ita sugar pill,” adds Hoven.

Physicians are frequently faced with complementary and alternative therapies that they know little about, and may ethically consent to their use, says Braddock, if the substance is not harmful and the physician offers full disclosure, something like this: “You seem to have a strong sense that this Ginkgo Biloba treatment could protect you from the onset of dementia. I don’t think it’s harmful. There is no evidence that it will work, but it may help you, so you can try it.”

AMA policy adds that physicians can avoid using a placebo, yet produce a “placebo-like effect through the skillful use of reassurance and encouragement. In this way, the physician builds respect and trust, promotes the patient-physician relationship, and improves health outcomes.”

Physicians can responsibly invite an ideal meaning response in patients by prescribing the least toxic drugs with the greatest enthusiasm, says Moerman.

Therapeutic Imperative

The placebo effect is a central part of the healing encounter between physicians and their patients, and physicians have an obligation to cultivate it in routine medical care – in some cases with adjunct therapies that may lack scientific backing, but certainly in the totality of the therapeutic transaction, advocates maintain.

An unintended outcome of the modern transformation of the medical care system has been to drive practitioners’ attention away from their patients’ experience of illness, according to Arthur Kleinman, M.D., professor of anthropology and psychiatry at Harvard University and Harvard University Medical School, and who also co-chaired the NIH’s 2000 conference on the science of the placebo. In a book published 20 years ago, The Illness Narratives: Suffering, Healing & the Human Condition, Kleinman maintains that the successful therapeutic relationship empowers and persuades the patient toward more successful coping, especially in chronically ill patients, for whom physicians have limited control over their diseases, and for whom even small changes in the perception of their symptoms and tolerance of their suffering can matter a great deal.

It is of the utmost importance that physicians achieve the highest possible placebo effect rates through relationships that resonate empathy and concern for the well-being of their patients, Kleinman writes. The disease-centered paradigm of contemporary biomedicine, in spite of remarkable progress in the control of disease, has largely turned its back on the role of placebo in the physician-patient relationship, and the recognition that the meanings that patients ascribe to their treatment affects what happens to them, he adds.

Over the 20 years since he wrote The Illness Narratives, “things have gotten a lot worse,” says Kleinman: physicians are even busier while the business and institutional structures of medicine, with their fixation on economics and efficiency, get in the way of caregiving – listening and attending to patients and the meanings of care.

“Medications and interventions carry meaning. When the physician is hopeful and supportive, and offers feeling of solidarity, the patient feels more humanized,” says Kleinman. “When we pull placebo out and make it an ethical question, we miss the boat for a red herring, while the ship of effective caregiving is sinking,” Kleinman notes. “The ethics of caregiving is a much more important issue, and that’s where our attention should be focused,” he adds.

Whether for active drugs with specific effect or adjunct treatments without specific effect, a physician can try to achieve the maximum “meaning impact” without deception, according to Kleinman. While the statement, “I can offer you vitamins, but they probably won’t work,” may undermine a placebo effect, he says, an equally honest alternative could maximize it: “You’ve got a complex problem and it’s unclear which treatment we should try. I’m here to help you. I have some vitamins you could try. They could help and could be a good addition to your treatment. Would you like to give them a try?”

Antidepressants, delivered within a supportive context, can carry a powerful placebo effect, says Kleinman, and several studies show relatively small differences between active antidepressant drugs (e.g., 65 percent effectiveness) and inert placebos (50 percent effectiveness) given in clinical trials. “We don’t pay attention to how to produce the maximum meaning impact. It’s crucial to balance treatment of the disease and treatment of the illness experience,” adds Kleinman.

Conversely, the magnitude of the placebo effect should not be overestimated, as it will not bring “enormous effects on significant diseases,” cautions Kleinman. But for the care of the chronically ill, he says, even a 10 to 15 percent change in function could make the difference between an asthmatic or an arthritic being able to return to work.

Neither must physicians overlook the power of meanings in life-threatening illnesses, such as with cancer patients who can easily become withdrawn and demoralized, says Kleinman. “Supportive caregiving is a crucial medical task even when you can’t change the disease,” Kleinman adds.

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