On placebos, placebo responses and placebo responders- (A review of psychological, psychopharmacological and psychophysiological factors), I- psychological factorsDR Doongaji, VN Vahia, MPE Bharucha
Department of Psychological Medicine, K.E.M. Hospital and Seth G.S. Medical College, Parel, Bombay-400 012, India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 364041
Source of Support: None, Conflict of Interest: None
Placebogenesis is an established phenomenon in the therapeutic management of virtually every known illness. This article reviews the various psychological factors which play an important role in the genesis of this important phenomenon. Classification of placebos along with ethical issues involved in administration of placebos for therapeutic and research purposes are discussed in the article.
Sir Oliver Wendell Holmes once remarked that 'if all the drugs are sunk to the bottom of the sea, it would be all the better for mankind, and all the worse for the fishes.' This statement is as applicable to the practice of therapy today as it was in bygone days. The enduring interest in placebos and placebo effects may be due to the fact that various substances which were used to treat ailments in the past, are known to possess no therapeutic properties today. It is this conclusion which probably led Shapiro to comment that the history of medicine is largely the history of placebo effects. 
In view of the present concept of 'specific remedies for specific illnesses' it is erroneous to consider the placebo a relic of the past. ,, Apart from its importance in clinical trials, the rationale and deliberate use of placebo still retains its value in modern medicine. Modell  wrote that placebo effect ".... is the only single action which all drugs have in common, and in some instances it is the only useful action which medications exert." A substantial portion of clinical medicine is virtually `placebo', meaning 'I shall please'.
The word placebo is derived from an ancient Biblical Hebrew phrase 'ethalekh' meaning 'I shall please'. This word was later replaced by the Latin 'placere' meaning 'to please'. 
The 18th century Motherby's New Medical Dictionary defined placebo as 'a common place method or medicine'.  A contemporary definition of placebo is 'any therapy (or that component of any therapy) that is deliberately used for its nonspecific psychologic or psychophysiologic effect, or that is used for its presumed specific effect on a patient, symptom or illness, but which, unknown to the patient and therapist, is without specific activity for the condition being treated'.  The placebo response has been defined a: the `non-specific psychologic or psychophysiologic effect produced by placebo"  or 'any effect attributable to a pill or potion or procedure, but not to its pharmacodynamic or specific properties'. 
The purpose of this review is to highlight certain aspects of this complex and confusing phenomenon which is associated with most therapeutic endeavours. ,,,,,,,,,,,,,,,,,,,,
Wolff et al  classified placebos into three groups:
1. Inert unpretentious substances-like lactose and starch.
2. Pseudomedicaments - extracts o: herbs, superfluous vitamins etc. These have been called 'impure placebos' i.e. the drug has therapeutic potential, but it is not indicated in the particular setting in which it is being tried.
3. The placebo effect-that goes along with the pharmacodynamic action of the therapeutic agent (e.g., even a small dose of an analgesic may produce significant relief in intense pain).
The incidence of placebo effectiveness is variously reported between 1% and 69% ,,,,,, Beecher  reviewed 15 studies chosen at random (involving 1082 patients). He found that the average effectiveness of placebo could be placed at 35.2 ± 2.2%. Beecher wrote that `The great power of placebos provides one of the strongest suppJrts for the view that drugs that are capable of altering subjective responses and symptoms do so to an important degree through their effect on the reaction component of suffering'. 
The deliberate use of placebo in any clinical trial raises an important ethical issue.  According to some authorities the administration of a placebo would amount to depriving a patient of his legitimate right to receive an established drug for a particular illness. , However if a placebo is administered when no specific cure for the ailment is known, or where the rationale of an established treatment regime is disputed, or where the illness is not likely to be fatal, the question of ethics can be favourably resolved.
1. Suggestion and Suggestibility
Traditionally, the placebo response was considered to be an example of hightened suggestibility, though this was not proved in experimental models. ,,
Eysenck  postulated that the characteristic `suggestibility' of an individual was made up of two unrelated components which he called 'primary suggestibility' and 'secondary suggestibility'. Primary suggestibility referred to the tendency to react to suggestion with motor movements e.g., on the body sway test, where the subject's degree of sway could be measured under the suggestion that he was falling forward. The second component i.e., secondary suggestibility referred to the inducement of feelings and perceptions in the subject. , One would expect this latter variety to be responsible for placebo-genesis. However the few studies on suggestibility which are there are mainly about primary suggestibility. They suggest a correlation between primary suggestibility and placebo response which was not found to be statistically significant. ,
Shapiro  himself was interested in exploring this relationship as the concept of suggestion and suggestibility is important in hypnosis. He devised some of his own studies and analysed the data from many authors. He found that the correlations between tests of suggestibility, tests of personality traits and the emergence of placebo responses were either inconclusive or contradictory. 
2. Patient's Expectations
Response to placebo treatment was found to be favourable when patients had a positive attitude towards medication and chemotherapy .  The subjects' ratings on "expectations of drug effect questionnaire" correlated significantly with subjective and behavioural criteria Of placebo reaction. 
Another trait which was 'studied was that of `acquiescence' or 'Yea-saying'. This may be defined as the tendency to respond in a pleasing or acceptable manner to others.  This trait correlated with the placebo response. However it was not shown to be associated with any particular personality type. It was found to be slightly more common in people with a conventional outlook, who held superficial views from which they could be easily swayed.  Individuals of this type were perhaps more accepting and less critical of the drug situation than the `Nay sayers', who tended to be more controlled and self-determined. 
4. Personality Tests
There are conflicting reports on the abilities of various tests to predict a placebo reactor. ,,,,,,,,,,,, Joyce  found that a short questionnaire derived from the Bernreuter Personality Inventory could be used to predict accurately whether a medical student would or would not react to a placebo. For a random study, knowledge of how an individual had reacted on a previous occasion was an extraordinarily successful predictor of subsequent behaviour. 
It is also interesting to note that those individuals who respond to a placebo when it is administered as a stimulant, have a different personality pattern (high extraversion score on the Maudsley Personality Inventory) when compared to those responding to a placebo which is given as a depressant. 
5. Motivation, Learning and Conditioning
These factors are important in the genesis of placebo responses as they are independent of transference. In a large number of studies which were reviewed by Shapiro  the results were not found to be conclusive.
Reliance in the treatment procedure, expectation and anticipation of relief, previous positive experiences with treatments and doctors, fame and popularity of the physician, and favourable expectations when coupled with any treatment were found to lead to a marked positive placebo effect. , Samuels and Edison  showed that negroes tended to respond to placebos more often than whites. This could be attributed to the prevalent attitude amongst the negroes to please their doctor.
De Grazea,  Frank,  Gumpert,  Haley,  Kiev,  Meerlo,  Murray.  etc. stated that relief of symptoms occurred when patients verbally expressed conflictual, guilty, and devious thoughts in a permissive and non-censorious atmosphere. Thus the crude primitive methods of producing catharsis have been replaced by more appropriate, sophisticated and intellectualised verbal methods. 
8. Defence Mechanisms and Phychodynamics
Some authors have discussed placebo effects in terms of psychodynamic defence mechanisms such as substitution, displacement, etc.  Various uncontrolled and non-specific factors also produce beneficial effects by offering reassurance to patients about their fantasies, fears of loss of control, fear of insantity, etc.  Various abreactive medicines like ingestion of alcohol, and compulsive overeating could also offer an outlet for anxiety. A patient may express his need to be cared for by a physician by requesting medication or reporting hypochondriacal symptoms. The ritual of taking medicine might in itself be warding off anxiety and reassuring the patient. 
9. Spontaneous Remissions
This factor must also be considered when placebogenesis is to be accounted for.
10. Personality Characteristics of Responders and Non-responders
The characteristics of negative responders and non-responders to placebo have not been defined adequately.
Negative responders are described as vague, non-specific, more rigid, hard to pin down, not responding to treatment,  self-controlled, but with less personality deviation than positive reactors.  Kurland  mentioned the adjustment of the individual as an important attribute of the placebo reaction.
According to Shapiro,  nonreactors are rigid, authoritarian, stereotypic, tend to use the mechanism of denial and are not psychologically oriented.
Finally, it is also reported  that positive reactors rely more on outer stimuli whereas negative reactors rely more on inner stimuli, and tend to have more paranoid and masochistic traits.
The authors thank Dr. C. K. Deshpande, Dean, K.E.M. Hospital and G.S. Medical College, for permission to publish this paper.