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We feel there are a number of factors involved in the patient's response to placebo but that the relatively outstanding feature was her previous experience of responding positively to the act of taking pills prescribed by doctors. As an indication of the pill-taking experience, the patient reported that each time she took a pill she was accustomed to thinking about how she felt, whether she was feeling better or not, and that these thoughts had a clearly positive flavor. A further question to be answered is why the patient was helped more by the placebo than by the tranquilizers she had taken previously. The fact that the therapist reminded her of her grandfather may have been an element. In addition, she seemed quite gratified to have grasped the paradoxical treatment situation by concluding we had given a drug. The patient was very satisfied with the idea of continuing with the same doctor and pills.
Following are brief excerpts of the study experiences for patients F, H, and S, who had doubts about the nature of the capsule contents. When "sugar pills" were introduced to patient F, she wondered if they worked in some way as a treatment for diabetes, mentioning her sister had this disease. Although it was clearly explained that there was no medicine of any sort in the capsules, the patient's last question in the initial interview was whether the medication would make her too drowsy. At the time of her final appointment, the patient reported she was markedly improved, feeling better than she had in over 20 years. She stated that although she believed she had been receiving placebo, she had noted that the contents of the capsules tasted sweet. The contents were actually tasteless. The patient indicated that she was quite suggestible, and she thought the treatment had been effective through a form of "hypnosis" because she had been told so many times she would improve.
Patient H was a 28-year-old man with a rather rigid personality pattern and little insight, who complained of irritability and temper outbursts for several months. At the first visit he indicated that placebo could not help. When he returned for visit two, the patient became aware of changes in his condition only as he was able to furnish satisfactory explanations for such change. Initially, he reported that there was essentially no improvement, stating that only ineffectual "hypochondriacs" are influenced by such pills. When questioned about specific symptoms, he became aware that he was less irritable, with fewer temper outbursts; lie pointed out that improvement had actually started even before he came to see us. He subsequently thought of two further explanations for improvement during the treatment week. The first was that he had helped himself. Also, he stated the pills might well contain a "mild tranquilizer," commenting that the doctor could have told him that they were placebo simply to make sure that he would take them. (He had a history of avoiding medication, having never taken pills in the past except for vitamins.) He categorically stated that if the pills were placebos they didn't help him, and if they were tranquilizers, perhaps they did; the explanation of the pills was basic to his grasp of the experience. In discussing these possible explanations for change which did not conflict with self-esteem, the patient recalled that for the first time in his marriage he had given his wife the "silent treatment" during a fight rather than losing his temper and that this brought a definite positive response on her part. He then realized that his obsessive, anxious preoccupation with a girl friend had been completely absent during the week of treatment. Finally, the patient was asked if taking the pills had reminded him to work on his problems, and he had an immediate "Aha!" reaction, reporting, "Every time I took a pill I thought of my doctor and how I'm doing. It just reminds me that you are trying to change yourself." At the end of the interview, his overall conclusion was that he had chiefly helped himself. It was noted that throughout this second interview, patient H was considerably more expressive and interactive than at the first appointment, with more affective and intellectual insight.
Patient S was a 32-year-old woman with Raynaud's disease who complained of tension symptoms which she attached to inability to stop smoking. She reported having taken a nonprescription type of drug which was supposed to help her to stop smoking but which only caused dry mouth. When placebo was introduced, she asked, "Why would it help, because for people, each time they take a pill, it's a symbol or something of someone caring about you, thinking about you three or four times a day?" When she returned for the second visit, the patient reported considerable improvement with regard to her anxious and apprehensive feelings, although she had been able to cut down only slightly on the smoking. She had noted considerable dry mouth during the treatment week, which she attributed to the pills. She felt the pills did not contain medicine in the usual sense, although they probably contained something "like a liniment." "I consider medicine something that will alleviate your symptoms, but this didn't alleviate the symptoms, just the desire to smoke." "Well, it's like these liniments that you rub on, the skin gets hot and makes the pain go." In further discussion, she indicated that the prescription by a psychiatrist of a pill containing nothing to help the anxiety symptoms brought to her awareness the thought that she could help herself. As a result of this, she made a number of changes in her environmental situation, which was quite at variance with her usual passive approach to problems.
Finally, the patient who dropped out of treatment, an anxious, depressed 45-year-old married woman, reported to the social worker at follow-up that she generally accepted the placebo and was feeling improved, primarily as a result of seeing the doctor, but that she became quite upset and discontinued the pills after her husband ridiculed and verbally attacked her for wasting her money on "sugar pills." At first she was angry with the husband, but subsequently she became increasingly depressed. There were no side-reactions to the pills. At follow-up, she expressed an interest in continuing the pills and in returning to the clinic but did not keep an appointment. It appeared that she was caught in an impossible bind between the hospital's approach and that of her husband.
Comment
From this study, we have learned that neurotic outpatients can be willing to take placebo even when the inert content is disclosed, at least in a situation presenting certain safeguards to them. In fact, many of the 15 patients appeared satisfied with the treatment; at least five patients desired to continue the placebo treatment and two felt no need of further treatment. One patient dropped out of treatment, but she manifested regret for having been talked out of continuing by her husband.
The study has shown that unawareness of the inert nature of the placebo is not an indispensable condition for improvement on placebo. It may here be argued that some general factors may have had a powerful influence in determining improvement "in spite of" the disclosure. An important consideration is the size of the sample, small enough to present the chance that a large percentage of individuals would be included who would have improved markedly under any treatment or even spontaneously. As Lasagna 15 points out, placebos, among other factors, "control naturally occurring, that is, spontaneous, changes in the course of disease" and "such a situation can be appreciated only if one contrives an experiment so that there are control periods for groups) when nothing of any sort is given and which may be compared with the placebo-treated period for group)."
In the analysis of results, it has been shown that 6 of 14 patients did not believe the capsules did not contain active drug, with three of them experiencing "side-reactions" they attributed to the pills. This was apparently related to the force of prior experiences, which at times induced patients to disregard or to disbelieve the doctor's assertion, and even played a role in determining physiological effects of taking the pills. This opens an important question regarding the limits of the capability of the experimenter, therapist, or teacher in influencing or changing established concepts in his trainees. The awareness of these limits is probably one foundation for the assumption that the patient should be led to believe the potency of placebo is due to chemical nature of a supposedly active drug. Jongbloed and Van Goor 9 were able to convince sportsmen who were inhaling bottled air that oxygen was administered to them and obtained better effort performances; then they administered pure oxygen to the sportsmen, telling them that it was simply air, and performances dropped. Of course, we do not know whether these authors would have obtained superior performances also if they had tried to convince the sportsmen that bottled air alone could improve such performances. The present study indicates this possibility.
The finding that the patients who had the most definite opinions as to the nature of the pills also showed the most improvement does not necessarily mean that a definite concept of the nature of treatment leads to a good response, since these same patients also came into the study with higher initial distress. Recent studies, including that of Uhlenhuth and Park,24 have demonstrated that patients with higher initial distress improve more (law of initial value). The findings of Beecher 1 that "the effectiveness of placebos is far greater when stress (pain) is greater than when it is less" may also be seen to indicate this trend. A possibly appropriate description for our findings may be that patients with higher initial distress and who show relatively marked improvement often develop quite definite ideas about the nature of treatment perhaps as the result of some need for a clear-cut frame of reference. The definite nature of these beliefs may be more important than their direction; it can be questioned how necessary it is for patients always to develop "correct" insight, insofar as "correct" insight is usually understood as the therapist's concept of the situation. The implication here is that a "faith" of some sort rather than a verifiable rationale is in some instances a more essential part of therapy, as has been illustrated by Frank.3
What general factors involved in the present study account for the fact that those patients who believed the pills were placebo improved as much as those who believed they were drug? Gliedman et al 4 write: "When placebos are employed, the achieved change in a patient's status may reflect his response to the particular doctor, or the doctor as symbolized by the medication, regardless of whether the medication was phamacologically active or not." The doctor may elicit "salutary changes in patients with appropriate prior experience," changes which "are probably transmitted by means of placebo." The treating doctors were quite enthusiastic about the study, optimistic in their statements, and at the same time quite anxious about telling patients that they would receive placebo. This combination of enthusiasm and alertness must have had a strong positive impact on the patients. It is also significant that Whitehorn25 suggests:
... To designate as "placebo" effects all those psychological and psychophysiological benefits or detriments which quite directly involve the patient's expectations and depend directly upon the diminution or augmentation of the patient's apprehension by the symbolism of medication or the symbolic implications of the physician's behavior and attitudes.
Under this viewpoint, the expectations of further and possibly different treatment at the end of the week of experimental treatment with placebo may be seen as a part of the placebo therapy.19 Gliedman et al 4 point out:
The animal learns to raise his leg because this has become a means for having food produced. Similarly, a patient may decide to meet his doctor's expectations because of anticipated rewards from him such as approval, respect, understanding, etc, provided the doctor meaningfully arouses him, ie, creates an appropriate central excitatory state. The use of placebo in these circumstances might function to reinforce symbolically such a doctor's effect in terms of the rewards the patient receives for modifying himself in accordance with his doctor's implied or direct recommendations. Patient changes ensuing after the use of placebo may obscure the role of the doctor, though it may be his presence, actually or symbolically, which makes these changes possible.
It would appear that the formulation of placebo effect as a response to the belief active medication is prescribed involves too narrow a view. A more comprehensive assumption would be that the basic requirement is general belief a situation defined as treatment might help, whatever its specific details.
The present placebo treatment could be viewed as having some affinity to psychotherapy not only in a manner similar to the "non-specific form of psychotherapy" which Rosenthal and Frank21 describe as "produced by the patient's faith in the efficacy of the therapist and his technique." Two major characteristics of accepted psychotherapeutic techniques 18 were present: on the one hand, support and reassurance were given, while, on the other hand, the responsibility for improvement was thrown back to the patient by means of the paradoxical statement that he needed treatment but that he could improve with a capsule containing no drug. How the combination of these two elements, support and autonomy, could benefit even a very distressed individual was dramatically illustrated in the case of patient T. His very positive response to the pills suggests the possibility that a negativistic, treatment oriented yet influence resistant patient might respond quite well to a doctor who prescribes a paradoxical treatment. Patient E had a similar experience. For patient H, a psychologically rigid individual, the ambiguous situation introduced broader thinking and feeling in much the same fashion as the posthypnotic experience or lysergic acid diethylamide (LSD-25) influences certain individuals. For patients C and S, statements that a pill with nothing in it might help brought to their awareness the thought they could help themselves. Finally, one patient responded favorably to a pill which could not be addicting (A) and another to the safety from suicidal risk (C).
The methodological issue of nonblind versus double-blind research can be raised with regard to the present study. The wealth of fascinating material gained by intensive evaluation of individual responses to information not presented to patients in double-blind psychopharmacological research speaks in favor of the study of the individual, in addition to statistical evaluation of checklists, and also strongly suggests the value of careful nonblind research. Human subjects are uniquely different from other research subjects in that they can judge and report, and this talent is frequently wasted in controlled studies. It is important to consider patients as part of the research team and to develop refined methodology for educating them to report valid data.19
Summary
Fifteen anxious, neurotic outpatients were placed on placebo treatment for one week after being informed the pills contained inert material. Fourteen patients took the pills and returned for the subsequent appointment, with all 14 reporting improvement; there was also overall marked improvement by doctor and patient ratings on several measures.
Eight patients stated at the subsequent appointment that they believed the pills were placebos, although only three patients were absolutely certain of this. Six of the returning patients thought the pills contained drugs, with two patients absolutely certain. Improvement was not related to belief in the nature of the pills but did appear related to certainty of belief.
The five patients dealing with the treatment situation in a relatively stereotyped manner patterned on previous doctor and medicine experiences tended to believe they were helped chiefly by an active drug. The other nine patients tended to believe they were helped by placebo, by themselves or by the doctor. For some of these latter patients, the paradoxical combination of verbal support with deliberately withheld medicinal support had psychotherapeutic implications.
The primary finding is that patients can be willing to take placebo and can improve despite disclosure of the inert content of the pills; belief in pill as drug was not a requirement for improvement. Methodological limitations and theoretical implications of these findings were discussed.
This study was supported partly by United States Public Health Service grant MH-04732.
Generic and Trade Names of Drugs
Amitriptyline hydrochloride—Elavil Hydrochloride. Meprobamate—Equanil, Equanil L-A, Wyseals, Meprospan, Meprotabs, Miltown.
Chlordiazepoxide hydrochloride—Librium.