Chapter 6 Placebo and the Power to Heal
Introduction
As time marches on, medicine has failed to stimulate and utilize the subliminal healing capacity of the mind. A recent review of placebo literature in Lancet1 concluded that the placebo effect has a complex physiologic multisystem dimension and should be encouraged in the clinical situation to optimize health and healing; a summary reached by this author 25 years ago. In November 2000, 17 health centers and agencies gathered together for 3 days to explore the science of self-healing hidden in the power of placebo. This conference focused on the powerful mind–brain physiology of placebo and its potential for affecting the course of human disease.2 One of the conclusions of the conference was that the “placebo response” has potential use for medical application and needs further exploration.
Research has shown that the impressions and thoughts in a patient’s mind and the attending physician’s intention have a measurable effect on the health of the patient. The ability of the patient’s mind to affect the process of virtually every disease has been well documented,3,4 and the internal mechanisms and pathways by which the mind can positively or negatively affect the immune and healing processes has been investigated in the scientific literature of psychoneuroimmunology.5,6 As the body of knowledge documenting the critical role of the patient’s psyche in the therapeutic environment has grown, it has become increasingly important for all schools of medicine to teach the healing potential of the human mind.
Conventional medical thinking has turned its opinion of placebo from that of a nineteenth-century pejorative to a concept that sums up the complex mind–body interactions affecting the power of people to heal.2 Unfortunately, the most modern abuse of the concept of placebo comes from biased critics of alternative medicine who have chosen to label the beneficial effects of these therapies as merely from placebo. These critics dismiss the science of natural healing as an imaginary phenomenon and the last resort for quack doctors who have no real medical treatments to offer their patients.7
The most interesting aspect of placebo literature is exploration of the extent of the potential of the mind to influence human health. The “power of placebo” draws upon the innate ability of the body to spontaneously heal itself, a fundamental principle of naturopathic medicine. This point separates the care delivered by naturopathic physicians from the pharmaceutical and surgical approaches of current medical “standard of care” procedures. If common medical texts on internal medicine or ambulatory care are examined, the word “healing” is not found in the index. Except for the diagnostic evaluation of “self-limiting diseases” and “spontaneous regression,” the ability of the human organism to self-right and repair from a state of acute or chronic disease is not explored in modern medicine except under the designation “placebo response.” The placebo response, therefore, represents all the “unknown” variables that conspire to heal a patient despite pharmaceutical and surgical intervention. Although it seems to be a natural area to develop in clinical and hospital settings, the fundamental separation of mind and body in conventional medical thinking may be slowing down a standardization of care that actively engages the hopes and beliefs of all patients undergoing treatment.
Placebo Response
Placebo response represents the power of the mind, through intention, to effect (1) a change in oneself, (2) a change in those around one, and (3) a change in the environment in which one lives. Intention has been observed to affect machines8 and remote biological systems.9 Distantly influenced systems include another person’s electrodermal activity, blood pressure, and muscular activity; the spatial orientation of fish; the locomotor activity of small mammals and the rate of hemolysis of human red blood cells. Prayer, an example of intention, has been extensively studied as a therapeutic healing modality.10 One study showed a dramatic result in cardiac intensive unit recovery when patients were prayed for by someone at a distant location.11 Patients in this study were 5 times less likely to require antibiotics, 3 times less likely to experience pulmonary edema, 12 times less likely to require endotracheal intubation, and significantly less likely to experience cardiac mortality.
Pierre Teilhard de Chardin postulated, and Rupert Sheldrake proved, the possibility of a “morphogenetic field” for the subliminal communication to all members of our species.12 The effect of human thought on other members of society has been described in human society since the beginning of our earliest cultures.
Why Study the Placebo Effect?
For hundreds of years, physicians have watched their patients respond to therapies with a wide range of results. Some patients recover fully, whereas others, with apparently identical diseases and therapies, wither and die. Today, a skilled physician can correctly diagnose the condition of a patient by applying the sophisticated techniques of modern medicine. Then, an appropriate therapy, the efficacy of which has been thoroughly proven in research and clinical trials, can be prescribed. Through this process the patient will have received the best care available through current medical technology. However, if the diagnosis, therapy, and therapeutic interaction do not stimulate the hope, faith, and belief of the patient, the chances of success are measurably diminished. It has been repeatedly demonstrated in the literature on the placebo effect,13 psychoneuroimmunology,5 and psychosomatic,14 behavioral,15,16 and psychiatric17 medicine, that the beliefs of both the patient and the doctor, and their trust in each other and the process, generate a significant portion of the therapeutic results.18
Because the doctor–patient relationship is such fertile ground for stimulating the healing response,19–21 it serves a physician well to comprehend the nature of the placebo phenomenon to fully realize this potential for healing.
History of Placebo
Both the modern physician and primitive medicine men and shamans of the past used ineffective therapies to stimulate healing in their patients. As Shapiro observed, “the true importance of placebo emerges with a review of the history of medical treatment.”22 It was noted that the historic therapies of the medical profession and traditional healers, “purging, puking, poisoning, puncturing, cutting, cupping, blistering, bleeding, leeching, heating, freezing, sweating, and shocking,”23 worked because of the placebo effect. Although in retrospect, these practices might seem ludicrous, all of these therapies were once considered effective. As an embarrassing epilogue, placebo literature showed that ineffective procedures are just as pervasive in modern medicine as in the jungle hut of the shaman. We must therefore ask ourselves how unfounded medical therapies can survive peer-reviewed literature and centuries of cultural acceptance.
The power of the patient’s belief in the potential for cure has been consistently observed throughout history. Both Galen and Hippocrates recognized the strong effect of the mind on disease and recommended that faith, treatment ritual, and a sound doctor–patient relationship could provide important therapeutic results.24 Recognition of the power of positive expectation was recorded frequently in the medical literature of the seventeenth and eighteenth centuries. It was in the eighteenth century that placebo was first defined as a “commonplace method of medicine.”25 As the importance of drug therapy grew in the nineteenth century, the term placebo became identified with medicines involving substances that resembled drugs. However, in the 1940s, because of the increase in double-blind research, it became associated with inert substances that were used to replace active medication.
Origin of the Term Placebo
The original Latin meaning of placebo is “I shall please.”26 Although the term had a purely medical application in the first half of the twentieth century, its meaning has been subject to various interpretations throughout the last several hundred years.
Before the 1940s, placebos were pharmacologically inactive substances, such as saline and lactose pills, used to satisfy patients that something was being done for them—in other words, the doctor was “pleasing” the patient. The 1940s and 1950s saw an explosion of the use of double-blind experimental procedures to evaluate the growing number of new drugs and medical procedures. Suspicion arose that all medical therapies contained an element of placebo phenomena.27 This new understanding pressed the scientific community to offer new, far broader definitions.
Shapiro23 offered the classic definition of a placebo:
Modern placebo definitions extend to its nature, properties, and effects. Placebo can be known or unknown, active or inactive, positive or negative in results (placebo effect vs nocebo effect), and can extend to all forms of diagnostic or therapeutic modalities28 as further defined in Box 6-1.
BOX 6-1 Types of Placebo
Known placebo: Placebo used in a single-blind experiment. The doctor knows it is placebo but the patient does not.
Unknown placebo: Double-blind use of placebo. Neither the doctor nor the patient knows that the medication is a placebo.
Active placebo: Any substance that has an intrinsic physiologic effect that is irrelevant to the ensuing placebo effect. The vasodilating effect of niacin would make it a good active placebo.
Inactive placebo: Any substance that is used with medicinal intent but that has no inherent physiologic effect. Aside from the glucose effect in a sugar pill (or, to complicate things, an allergic reaction to some component of the supposedly inert substance), it has no physiologic effect.
Placebo effect: Any changes that occur in a patient as the result of placebo therapy.
Nocebo effect: Any changes that occur as a result of placebo therapy that are perceived as negative or counterproductive to the path of cure.
Clinical Observations of “Known” Placebo Therapy
One of the more dramatic examples of the placebo effect reported in the medical literature involved a patient with advanced lymphosarcoma, which Klopfer29 reported was highly susceptible to the patient’s faith in an experimental drug called Krebozion. When the patient was started on the drug injections, his enthusiasm was so intense that “The tumor masses had melted like snowballs on a hot stove, and in only a few days, they were half their original size!”29 The injections were continued until the patient was discharged from the hospital and had regained a full and normal life, a complete reversal of his disease and its grim prognosis.
With much pomp and ceremony, saline water placebo was injected, increasing the patient’s expectations to a fevered pitch. Recovery from his second near terminal state was even more dramatic than the first. Tumor masses melted, chest fluid vanished, he became ambulatory, and even went back to flying again. At this time he was certainly the picture of health. The water injections were continued, since they worked such wonders. He then remained symptom free for over two months. At this time, the final American Medical Association announcement appeared in the press—“nationwide tests show Krebozion to be a worthless drug in the treatment of cancer.” Within a few days of this report, the patient was readmitted to the hospital in extremis. His faith was now gone, his last hope vanished, and he succumbed in less than two days.29
Other famous placebo case studies are one reported by Cannon30 on “voodoo death” caused by belief, and one reported by Kirkpatrick,31 who documented the spontaneous regression of lupus erythematosus resulting, in part, from the patient’s belief in the removal of a curse.
Other Clinical Observations
Belief sickens, belief kills, belief heals.32
Evans33 and Beecher34 reviewed, between them, 26 double-blind studies on the efficacy of active analgesic drugs in the treatment of pain. Independently, they concluded that 35% of patients with pain experienced a 50% reduction in their symptoms after placebo medication. These were particularly remarkable results when viewed in the context of Evans’s observation that with a standard dose of morphine, only 75% of the patients experienced a 50% reduction in pain. In calculating the efficiency index of placebo analgesia, a method often used to determine the relative efficiency of drugs, placebo was 0.56 as effective as a standard dose of morphine. This prompted Evans to remark, “Thus, on average, placebo is not a third as effective as a standard injection of morphine in reducing severe clinical pain of various kinds but is in fact 56% as effective.”33
As discussed previously, placebo has been evaluated in a wide variety of clinical settings in addition to pain management (Box 6-2). When a phenomenon such as placebo has been observed to be active in diverse clinical situations, such as surgery, drug therapy, psychotherapy, and biofeedback, and over a range of physical and mental symptoms, the conclusion that it must be a factor in all aspects of medicine is inescapable.
In addition to the variety of positive effects that placebo produces are the nocebo effects, perceived as counterproductive to the therapeutic goals. These side effects are frequently consistent with those of the medication that patients believe they are getting. For example, the studies that measure the effects of a supposed aspirin usually show nocebo effects of ulcerlike pain.41
In homeopathy, aggravations and ameliorations are commonly seen when a placebo is given to fend off a patient’s need to take a medication while the homeopathic physician is waiting to see whether a high-potency remedy will effect a cure. Homeopathic doctors report that placebos can cause anxiety and loneliness as well as calmness and immediate relief from insomnia.42
Placebo Myths
Investigation of the understanding of placebo found in the current medical literature revealed the misconceptions that prevail about the nature of placebo therapy and its effectiveness.42 A study undertaken to examine doctors’ and nurses’ attitudes about the efficacy and use of placebos showed that both groups underestimated the number of patients who could be helped by placebo.43 Physicians showed a consistent pattern of placebo use, as follows:
• Placebos were used to prove the patient wrong through diagnosis of psychogenic symptoms in patients who were thought to be exaggerating, imagining, or faking their symptoms.
• Placebos were used in the treatment of alcoholic, psychotic, and demanding patients who were disliked by the staff of the hospital.
• Placebos were used as treatment in situations in which standard treatments failed or the patient was getting worse.
Myths about placebos continue to hinder full understanding about the power inherent in this aspect of health care. The most common myths are discussed here.44
Myth 1
Fact. Research showed that placebos have a wide range of effects (Table 6-1) that are found throughout all aspects of human physiology.
TABLE 6-1 Physiologic Changes Induced by Placebo
| PHYSIOLOGIC FUNCTION | PHYSIOLOGIC CHANGES |
|---|---|
| Heart | Improved exercise tolerance45,46 Decreased serum lipoproteins47 Improved T waves48 Decreased pulse rate and arterial pressure49 |
| Sympathetic stimulation | Decreased tremulousness, sweating, and tachycardia36 |
| Claudication Opiod dependence | Increased walking distance50 Addictive drug withdrawal51 |
| Postsurgical trauma | Decreased facial swelling52 |
| Diabetic blood sugar dyscrasias (NIDDM) | Lowered fasting blood sugar53,54 |
| Gastrointestinal secretion and motility | Decreased gastric acid secretion55 Changes in gastric motility56,57 Healing of duodenal ulcers58 |
| Hypertension | Lowered blood pressure59–61 Reduced urinary catecholamines62 |
| Motor dysfunction | Improved tremor magnitude63 |
NIDDM, non–insulin-dependent diabetes mellitus.
Myth 2
Beecher18 was one of the first to compile a listing of the therapeutic effectiveness of placebo, thereby uncovering the wide range of therapeutic applications that were previously thought to be limited to only pain control. He concluded, “there is too little scientific as well as clinical appreciation of how important unawareness of these placebo effects can be and how devastating to experimental studies as well as to sound clinical judgement lack of attention to them can be.”18
The large and ever-growing number of studies on placebo and double-blind research (Box 6-3) supports the following assertion made by Beecher18 30 years ago:
Many “effective” drugs have power only a little greater than that of placebo. To separate out even fairly great true effects above those of placebo is manifestly difficult to impossible on the basis of clinical impression. Many a drug has been extolled on the basis of clinical impression when the only power it had was that of a placebo.
Myth 3
“The placebo effect is found only in substances that are inert.”
Fact. Placebo phenomena have been observed across a wide spectrum of medical disciplines, including surgery,102 drug therapy,103 and biofeedback.104
Myth 4
“The patient who responds to placebo can be characterized as someone who is of a typical neurotic disposition.”43
Fact. Although many studies have tried to impute a personality type, disposition,104,105 or certain epidemiologic class106 to the patient who responds to placebo, this has yet to be well demonstrated, because given the right circumstances, any person can become a placebo reactor.107,108
After reviewing the bulk of the research on this subject, Bush109 and Wolf and Pinsky36 concluded that the attempts to pigeonhole personalities into a clinical profile ignored the complexity of the human mind. Gliedman et al98 similarly reported that age, sex, marital status, social class, and intelligence were unimportant factors in determining a patient’s response to placebo. Wolf summarized that attempts to identify placebo reactors need to
“identify the nature of the symptom being treated, the motivation of the patient and physician, the nature of the test agent, its mode of administration and the life situation of the subject at the time he is tested. The significant point here is not the apparently conflicting findings of investigators with respect to placebo reactors, but rather that in any given situation, responses to a placebo may vary as compared to any other situation and the significance of situations to human subjects cannot be precisely duplicated.”36
Pharmacodynamics
The physiologic response of the “inert and inactive” placebo extends into the realm of drug pharmacodynamics. Dose–response time curves, cumulative effects (increasing therapeutic efficacy with repeated doses),110 variable strengths of analgesia based on a patient’s drug expectation,64 drug interactions,36,111 and carryover effects39,105 have all been demonstrated. The effects of placebo are so pronounced that some observers have suggested that they can exceed the effects attributable to potent pharmacologic agents.36
Packaging and Delivery
Several studies found that the effectiveness of placebo therapy depends on the mode of delivery.48 For example, one study found that green tablets improved anxiety and yellow tablets improved depression,112 whereas another study found that blue capsules were more sedative and pink capsules were more stimulating.49 Placebo injections appeared to be more effective than oral administration after oral placebo failed to relieve the symptoms.41
Placebo Interactions
Benson113 wrote that the patient’s belief was also a powerful force in determining the level of relief afforded by the placebo. An increase in patient expectation enhances the physician’s ability to elicit a placebo response. Even if patients know that they are receiving placebos, the expectation and relief brought about by the therapeutic interaction provides positive results.114 The importance of expectation was further demonstrated by the observation that the greater the stress level of the patient and the greater his or her need for assistance, the greater the effectiveness of placebo.38 This was seen even in patient responses to psychotropic drugs: D-lysergic acid diethylamide tartrate 25 (LSD-25) could have no effect if the patient was told that the drug was a placebo.104,115
Patients, such as war heroes, who had severe injuries but did not have great mental suffering attached to their pain needed less pain medication than persons with similar injuries who had pain that engendered anxiety and connoted disaster.116
Placebo Healing Mechanisms
When animals or humans can react to their own deviations from homeostasis and when these deviations set off restorative processes, therapeutic intervention, including placebo, has an already existing substrate of recovery for exploitation.15
A human being has an intrinsic ability to “self-right”—vis medicatrix naturae (the healing power of nature). This is the keystone of a philosophy that has been held for thousands of years by naturally oriented physicians (see Chapter 5). The concept of a homeostatic, self-regulating mechanism is central to the understanding of basic concepts of physiology: negative feedback loops control virtually all systems of the body. According to Guyton,117 “the body is actually a social order of about 75 trillion cells organized into different functional structures.… [E]ach cell benefits from homeostasis and in turn each cell contributes its share toward the maintenance of homeostasis.”
The body can maintain health and reestablish a healthy state after disease by virtue of its inherent vitality. This is part of the definition of a homeostatic mechanism; it has been selected by nature in the same way that organs vital to our survival have been selected. The surviving species are those most fitted and best able to cope with dysfunction. Those organisms that can tolerate the greatest stresses and still maintain a normal physiology are the hardiest survivors and ensure the species’ ability to increase the limits of its adaptation. Therefore, given that an organism is self-maintaining when in an environment that it has been selected for, healing happens unaided through simply maintaining an environment that does not obstruct the path of cure. As Norman Cousins118 observed, “without any help, the human body is able to prescribe for itself. It does so because of a healing system that is no less real than the circulatory system, the digestive system, the nervous system, or any of the other systems that define human beings and enable them to function.”
The Role of Emotions
Starting in the 1970s and early 1980s, review articles began to examine the effect of the mind on the immune system, emphasizing mechanisms and pathways that gave rise to a new field called psychneuroimmunology.4 Reviews of studies that explored how specific emotions can increase cancer susceptibility,119,120 examined the effect of emotions and recovery from cancer,121 investigated the increased incidence of sudden and rapid death during psychological stress,122 and monitored the changes in immune function during emotional stress123,124 all confirmed that emotions play a powerful role in the prognosis of a patient. Cannon30 and Tregear125 documented dramatic case histories of pioneering anthropologists who witnessed the power of taboos and curses to kill strong healthy men and women in third world cultures throughout Africa, South America, and the South Pacific. Tregear125 wrote, “I have seen a strong young man die the same day he was tauped [tabooed]; the victims die under it as though their strength ran out as water.”
The Vis Medicatrix Naturae
The healing process described as vis medicatrix naturae demonstrates the significant power and potential of the self-generated healing capacity. For a physician, there is no more powerful stimulator of this healing mechanism, the placebo effect, than a strong doctor–patient interaction. Just walking through the door of the physician’s office nudges a patient’s internal homeostatic mechanisms into seeking higher levels of health, healing, and adaptation. The placebo effect is a result or effect of the patient’s seeking the assistance of the doctor’s ability to heal and cure. As Benson113 noted:
Conscious Control Over Homeostasis
The body has two internal forces to maintain homeostasis: a lower drive and a higher drive. The lower drive is the inherent internal healing mechanism, the vital force, or the primitive life support and repair mechanism that can operate even in a person who is asleep, unconscious, or comatose. The higher drive is the power of the mind and emotions to intervene and affect the course of health and disease by depressing or stimulating the internal healing capacities. The effect of this drive can be seen in the clinical observation of patients who move toward spontaneous remission of a life-threatening disease through positive emotional support13,121 and in patients who fail to express emotions compatible with the body’s attempts to survive.121
In any disease process, the consciousness of the patient decides the effectiveness of any therapy. It has been suggested that a wide range of nondrug stimuli has the capacity to modulate human functioning.126 It is emerging in medical literature that any sensor stimuli or mental activity is able to alter disease progression. This extends to the thoughts and intentions of those connected to the patient. Experiments in remote intention-generated healing and prayer showed that the intention of others was a factor in the homeostatic capabilities of the mind and body. The fact that the homeostatic mechanism can sense and respond to these remote intentions is a reflection of the power of the human mind. Some authors believe that there is a physiologic basis for the unlimited possibility of human voluntary control.127 The conclusion that awareness or “mind,” anyone’s mind—the patient, the doctor, or someone who is aware of the patient—can alter the patient’s physiology is testament to the “holos” concept in different schools of alternative and complementary medicine. This idea flies so deeply in the face of our mechanistic model of medicine, it forces a complete paradigm shift in the conventional social ethos of medical care.
The ultimate control of psyche over soma demonstrates the priority of the conscious mind over physiologic processes such as immunity and pain control.128 This puts an enormous responsibility on the physician. He or she must take full account of a patient’s mental and emotional states when treating chronic or life-threatening disease.
Physiologic Mechanisms
Identification of a biochemical mechanism for placebo analgesia has done more to change the image of placebo than any amount of arguing about the importance of beliefs and the mind.129
The mechanisms of placebo response have been suggested to be a mixture of psychological interactions mediating physiologic responses.17 Psychological components of the patient’s placebo effect have been shown to include decreased anxiety and increased relaxation,64 conditioning,16 expectation,21 and well-being generated by the establishment of a sound doctor–patient relationship.130,131
Review articles summarized a wide range of receptor agonist mechanisms driving the neural pathways in different parts of the brain.132 To date, endorphin, dopamine, cholecystokinin, interleukins, growth hormone, and cortisol have been implicated. The physiologic mechanisms of the placebo effect were suggested to include chemicals, catalysts, and enzymes. It is believed that steroids, catecholamines,13 the autonomic nervous system,17,133 neuropeptides, and endorphins134 are also involved. These physiologic mechanisms interrelate synergistically and are rapidly being researched within the rapidly developing field of psychoneuroimmunology,6 through which the links between depression, affective disorders, emotions, and the immune system and central nervous system (CNS) are being explored. Susceptibility to depression and sensitivity to pain have now been found to be mediated through neurotransmitters such as catecholamines, serotonin, and dopamine.
The current model for explaining the mechanism by which emotions, mood, and psychological stress suppress immune function involves cerebral–hypothalamic and pituitary interaction, which translates stress and anxiety into an autonomic–endocrine response. This response adversely affects the immune function, particularly after chronic stimulation. Stressful stimulation is received in the sensory cortex of the brain and is then referred to the limbic system and the hypothalamus. This interface of higher brain functions and homeostatic regulating centers provides the communication link between the psyche and soma. According to Rossi,17 “The hypothalamus is thus the major output pathway of the limbic system. It integrates the sensory-perceptual, emotional, and cognitive function of the mind with the biology of the body.”
The nerve centers that control both branches of the autonomic nervous system (both parasympathetic and sympathetic), nerve cells that secrete endocrine-releasing factors, and neural pathways that release hormones directly into the posterior pituitary are in the hypothalamus. The corticosteroids and catecholamines from sympathetic stimulation are key factors in the alteration of disease susceptibility in response to stress. Corticosteroids inhibit the function of both macrophages and lymphocytes, as well as lymphocyte proliferation.135 Corticosteroids also cause the thymic and lymphoid atrophy noted by Hans Selye in his experiments on stress-induced immune dysfunction.136
The autonomic release of catecholamines stimulates receptors on the surface of lymphocytes, thereby increasing their maturation rate. When lymphocytes are in a mature state, their ability to kill bacteria and cancer cells and produce interferon seems to become paralyzed.137 Thus a population of mature lymphocytes develops, ready to defend the body from infection and inflammation, yet remains paralyzed until the “red alert” signal of sympathetic fight or flight is turned off, signaling the appropriate time to rest and repair.
A number of other peptides, E-type prostaglandins, somatotropin, histamine, insulin, endorphins, antidiuretic hormone, and parathyroid hormone all have receptor sites on lymphocytes and can stimulate the same cyclic adenosine monophosphate mediated response resulting in lymphocyte maturation and inhibition.135 A study of the effect of catecholamines on the human immune system showed that when a physiologic dose of epinephrine was injected into a healthy volunteer, there was an increase in the number of circulating suppressor T lymphocytes and a decrease in the number of circulating helper T lymphocytes (changes similar to those found in acquired immunodeficiency syndrome [AIDS]).135
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