“One should treat as many patients as soon as possible with the new drug while it still has power to heal.”
The era of placebo research began in 1955 with Henry Beecher’s1 pioneering study in which the occurrence of placebo effects was described. The following year, Beecher published a study comparing requests for morphine for unbearable pain in combat zone injuries with similar injuries in the subjects’ civilian counterparts (25% versus 80%). Beecher argued that subjective experience of the meaning of injuries (future financial difficulties in civilian life versus safety away from combat zone) may have explained the difference in demand for morphine.2 Thus began the era of exploring the psychology behind placebo effects.
Most placebo research is derived from studies on pain and pain perception, but one should note that placebo and nocebo effects also occur in other medical conditions. Placebo is not a unitary phenomenon, nor does it occur in a vacuum. It is dynamic and acts synergistically with other therapeutic elements. The common mediators of placebo effects are listed in Table 1.
Common Mediators of Placebo Effects
By definition, expectancy is the patient’s intensity of expectation that he or she will be helped by the treatment. In therapeutic contexts, it is the cornerstone of understanding the trigger of placebo response in an attentive and engaged patient.
Verbal suggestions are powerful in activating expectancy response. In a three-arm study of verbal instructions by Polo et al.,3 postsurgical patients received baseline infusion of intravenous saline and buprenorphine on demand for pain management. Group one was natural history control (those who were told nothing). Group two simulated double-blind conditions (patients were told they would receive either a powerful analgesic or a placebo). Group three simulated the “deceptive” condition (patients were told that the basic infusion was a powerful analgesic). Group three requested and received 33% less buprenorphine, and group two received 20% less drug compared with group one.
Stone et al.4 manipulated the expectancies of patients with Parkinson’s disease who were receiving placebo by telling them the probable chances of receiving active medication. Significant dopamine release occurred when the declared probability of receiving active medication was 75%, but not at lower probabilities.
Physician expectations can also be modulated by altering their beliefs, which in itself subtly shapes placebo response in patients. In one study of patients with postoperative dental pain, different sets of information were given to the patients and the physicians; however, the patients were not aware of the different information given to the clinicians. The patients received fentanyl or placebo under double-blind conditions. The clinicians were informed that active drug condition was not possible in one group. Placebo response was dramatically less in the group in which clinicians believed that no analgesic therapy could be given.5
Similar findings are evident in meta-analysis of placebo-controlled antidepressant trials. Expectation of being in an active treatment group appears to improve response rates for trial participants across treatment arms, whereas the presence of a placebo group tends to decrease response rates in those receiving the active drug intervention.6 The presence of side effects in active placebo groups can send expectations soaring and produce drug-like responses.7
The commercial marketplace can also manipulate patients’ expectancy. One study found that subjects experienced greater pain reduction from a placebo analgesic when they were instructed that the drug cost was $2.50 per pill than when they were told it had been discounted to $0.10 per pill.8
Ego-developmental psychology stresses the importance of early childhood experiences in shaping the way we think about healing. An infant gradually gains the capacity to self-soothe through repeated nurturing interactions with the mother, which modulates infants’ level of autonomic nervous system arousal and future emotional well-being. The child uses transitional objects on his or her way to developing a central affective state of well-being to become an emotionally self-reliant individual. Kradin9 suggested that in therapeutic settings, placebos act as transitional objects by promoting states of well-being. He saw it as an opportunity to rekindle the dormant soothing pattern of an early interaction with a caregiver, where the relationship is more important than any specific treatment provided. Prescriptions, pills, worksheets, or medical devices may function as proto- symbols, mediating between the suffering self and the world to promote the patient’s sense of autonomy and self-efficacy.10
Freud believed that positive dynamics of the analytic relationship created powerful transference feelings, which became one of the many engines that promoted cure. He also stressed the power of suggestion in psychotherapy: “The gold of psychoanalysis needs to be strengthened by the copper of suggestion.” Positive transference may also contribute to the reduction of stress and anxiety and increase positive emotions.11
Desire, belief, and expectancy combine to produce hope, which in itself is a potent mediator of the placebo effect. Hope can consciously or unconsciously motivate people to follow health-promoting behaviors (ie, proper nutrition, exercise, stress reduction, skills training, adherence to therapeutic regimen). The coronary drug project showed lower mortality in compliant patients, even in the placebo-treated group.12
Expectation also plays a major role on subjective and behavioral effects of the drugs acting on the central nervous system. Cocaine addicts expecting methylphenidate and getting it produced much larger clinical benefit than when they received it without expectant anticipation.13
This mechanism is well-documented in pain, but also in unconscious physiological processes affecting the immune system, the endocrine system, and hormonal secretion.14
Pharmacologically conditioned placebo responses mimic drug effects — placebos given after drugs are more effective than placebos given for the first time. The higher the number of administrations of a drug, the more robust a response a placebo will produce when given afterward.15 This type of associative learning has been successfully exploited in two clinical trials. Ader et al.16 treated patients with severe psoriasis using a partial reinforcement drug group, in which a full dose of corticosteroids was given 25% to 50% of the time and placebo medications were given other times. The investigators observed similar relapse rates in the full-dose treatment (22.2%) and partial-reinforcement groups (26.7%), suggesting that a regime of reinforcement can garner significant benefits.
Another example of conditioned pharmacotherapy effects outside the realm of the immune system was seen in a study by Sandler et al.17 In this three-arm study that lasted 8 weeks, children with attention deficit hyperactivity disorder were divided in three groups. One group received full-dose treatment with amphetamines, a second group received a 50% dose with open reduction of the drug, and the third group received parentally authorized placebo pills with a 50% reduced dose of amphetamines. The placebo reinforcement allowed children to be treated effectively with a lower dose of stimulant medication. If replicated for other conditions, these two studies have the potential to become the basis for a specific method to promote placebo response in routine clinical practice. Integrating the placebos in schedules of reinforcement can reduce the side effects and cost of treatment while maintaining therapeutic benefits. Both expectancy and the conditioning mechanism intermingle with previous experience of either positive or negative outcomes in producing placebo effects in clinical practice. As stated by Finnis et al.,18 “expectancies first, conditioning follows and is dependent on the success of the first encounter.” The successful clinician is able to harness heightened expectations during first visit and transform that force into conditioning effects of benefit with future visits.
Social and observational learning is a form of associative learning based on human social interaction. The magnitude of observationally induced placebo response appears to be similar to those responses produced by first-hand experience. People with a higher capacity for empathy appear to have greater propensity for observation-induced placebo response. On the flipside, in clinical studies with placebo control, side effects observed in the placebo arm often imitate the drug arm transmitted via the instrument of informed consent.
The psycho-social processes involved in placebo response are not peculiar only to placebos; they apply to any treatment. The symbolic, affective, and sensitivity experiences in human societies are shaped by experiencing by an individual in the crucible of cultural and biological milieu. Thompson et al.19 called this “embodied learning and contextual responding.” This type of learning is independent of conscious awareness.
The therapeutic relationship is considered to be the most important component in promoting placebo effects. Patients often go “doctor shopping” to find the right expert well-suited to generate confidence in them (based on reputation and/or pedigree) rather than due to a general desire to find a good relationship. The very presence of a physician may increase the magnitude of the placebo effect.
Patients’ direct experience with the doctor as likable and credible strengthens the expectations of efficacious treatment and makes it likely that placebo effect will occur.20 In family practice and psychiatry, where recurring contacts between the same doctor and patient are the norm, research indicates that the greater empathy and positive information the patient receives from the doctor, the greater the placebo effect. Brody writes that by providing an understandable and satisfying explanation of the illness, demonstrating care and concern, holding out hope, and promise of mastery of control over symptoms, personal suffering is given socially acceptable meaning.21 This is of enormous value to the patient and can be the well spring of the placebo effect.
Physician Attitudes and Communication
An intelligible account of the illness, the diagnosis, and the prognosis itself may be a form of therapy.22 Providing the name of the malady is the first step toward controlling it, which makes the doctor the “transmitter of an impressive healing force.”23
Thomas,24 a general practitioner, was an advocate for positive framing of the diagnosis. In his study, patients who were given a specific diagnosis and told they would get better did in fact get better, more frequently than those not given a diagnosis. In the same study, ordering a diagnostic test appeared to improve patients’ well-being and satisfaction, but prescribing a drug as part of management had no impact on the outcome. In another study of response to anti-anxiety medication in 138 patients, positive and enthusiastic clinicians produced more significant effects on outcome than tentative and uninterested clinicians.25
Placebo effects are not solely limited to placebo pills. When the physical characteristics of the drugs account for more than the chemical ingredients of the medication, these may be called meaning effects. Table 2 summarizes some of these qualities.
Efficacy is in the Mind of the Believer
Meaning effects appear to be driven by unconscious symbolic or iconic images. Moerman,29 a champion of re-framing placebo response as “meaning response,” has scoured the placebo literature for meaning-related variables. In one study of the influence of culture, for example, he found more placebo responsiveness in peptic ulcer relief for German patients than Danish or Dutch patients.29 In another study, he showed decreased efficacy of older branded drugs over time as new ones came to the market.33 Introduction of a new drug generates rousing enthusiasm, inflating response from expectancy effect.
The Healing Ritual
Starting with Jerome Frank23 in 1961, psychologists have also explored the ritualistic aspect of healing related to placebo effects. In a three-arm study of 262 patients with irritable bowel syndrome (IBS), Kaptchuck et al.34 demonstrated that even fake acupuncture enhanced by empathic and supportive communication could produce adequate symptom relief. Incremental doses of quality and quantity time with acupuncturists produced a gradation of response: Minimal supportive communication produced a 28% response; moderate time communication produced a 44% response; and maximal augmented, scripted communication of 45 minutes produced a 62% response. Interestingly, immunological biomarkers were expressed in the serum of augmented relationship patients as robustly as with any medicine ever tested for IBS.
Frank23 argued that positive expectations based on a “shared assumptive world” reduced demoralization and also came to see the role of persuasive communication in successful therapy outcome.
Anthropologists have explained the healing power of the ritual of healing as social or performative efficacy. Sham surgical procedures arguably use performative efficacy to produce robust placebo effects.19
In a trial of arthroscopy surgery for osteoarthritis of the knee, there was no difference in pain improvement between those getting actual procedure and those getting incision and sutures only. Furthermore, improvement was maintained in all groups after a 2-year follow-up.35
A National Institutes of Health conference in 2000, which included 500 scientists, researchers, and other drug company manufacturers, on placebo effects concluded that there are no unique personality trait responses to promoting placebo effects. However, some recent studies have found that optimists respond better than pessimists,36 extroversion and openness helps in responding to placebos,34 and those with acquiescing personalities who develop positive relationships with others and use them as healing resources are placebo-response prone.37
In conclusion, psychological explanations for placebo effects are diverse, ranging from expectancies to conditioning, learning to motivation, and reward all within the framework of therapeutic relationship. They elucidate our understanding of symptom relief and coping with illness.
- Beecher HK. The powerful placebo. J Am Med Assoc. 1955;159(17):1602–1606. doi:10.1001/jama.1955.02960340022006 [CrossRef]
- Beecher HK. Relationship of significance of wound to pain experienced. J Am Med Assoc. 1956;161(17):1609–1613. doi:10.1001/jama.1956.02970170005002 [CrossRef]
- Pollo A, Amanzio M, Arslanian A, et al. Response expectancies in placebo analgesia and their clinical relevance. Pain. 2001;93(1):77–84. doi:10.1016/S0304-3959(01)00296-2 [CrossRef]
- Lidstone SC, Schulzer M, Dinelle K, et al. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry. 2010;67(8):857–865. doi:10.1001/archgenpsychiatry.2010.88 [CrossRef]
- Gracely RH, Dubner R, Deeter WR, Wolskee PJ. Clinicians’ expectations influence placebo analgesia. Lancet. 1985;1(8419):43. doi:10.1016/S0140-6736(85)90984-5 [CrossRef]
- Papakostas GI, Fava M. Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol. 2009;19(1):34–40. doi:10.1016/j.euroneuro.2008.08.009 [CrossRef]
- Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants for depression. Cochrane Database Syst Rev. 2004;(1):CD003012.
- Waber RL, Shiv B, Carmon Z, Ariely D. Commercial features of placebo and therapeutic efficacy. JAMA. 2008;299(9):1016–1017. doi:10.1001/jama.299.9.1016 [CrossRef]
- Kradin R. The Placebo Response and the Power of Unconscious Healing. New York, NY: Routledge; 2008.
- Straus JL, von Ammon Cavanaugh S. Placebo effects. Issues for clinical practice in psychiatry and medicine. Psychosomatics. 1996;37(4):315–326. doi:10.1016/S0033-3182(96)71544-X [CrossRef]
- Flaten MA, Simonsen T, Olsen H. Drug-related information generates placebo and nocebo responses that modify the drug response. Psychosom Med. 1999;61(2):250–255.
- Simpson SH, Eurich DT, Majumdar SR, et al. A meta-analysis of the association between adherence to drug therapy and mortality. BMJ. 2006;333(7557):15. doi:10.1136/bmj.38875.675486.55 [CrossRef]
- Volkow ND, Wang GJ, Ma Y, et al. Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. J Neurosci. 2003;23(36):11461–11468.
- Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron. 2008;59(2):195–206. doi:10.1016/j.neuron.2008.06.030 [CrossRef]
- Colloca L, Miller FG. Harnessing the placebo effect: the need for translational research. Philos Trans R Soc Lond B Biol Sci. 2011;366(1572):1922–1930. doi:10.1098/rstb.2010.0399 [CrossRef]
- Ader R, Mercurio MG, Walton J, et al. Conditioned pharmacotherapeutic effects: a preliminary study. Psychosom Med. 2010;72(2):192–197. doi:10.1097/PSY.0b013e3181cbd38b [CrossRef]
- Sandler AD, Glesne CE, Bodfish JW. Conditioned placebo dose reduction: a new treatment in attention-deficit hyperactivity disorder?J Dev Behav Pediatr. 2010;31(5):369–375. doi:10.1097/DBP.0b013e3181e121ed [CrossRef]
- Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet. 2010;375(9715):686–695. doi:10.1016/S0140-6736(09)61706-2 [CrossRef]
- Thompson JJ, Ritenbaugh C, Nichter M. Reconsidering the placebo response from a broad anthropological perspective. Cult Med Psychiatry. 2009;33(1):112–152. doi:10.1007/s11013-008-9122-2 [CrossRef]
- Vase L, Nørskov KN, Petersen GL, Price DD. Patients’ direct experiences as central elements of placebo analgesia. Philos Trans R Soc Lond B Biol Sci. 2011;366(1572):1913–1921. doi:10.1098/rstb.2010.0402 [CrossRef]
- Brody H, Brody D. The Placebo Response: How You Can Release the Body’s Inner Pharmacy For Better Health. New York, NY: Cliff Street Books; 2000.
- Brody H, Waters DB. Diagnosis is treatment. J Fam Pract. 1980;10(3):445–449.
- Frank JD, Frank JB. Persuasion and Healing: A Comparative Study of Psychotherapy. Baltimore, MD: Johns Hopkins University Press; 1991.
- Thomas KB. General practice consultations: is there any point in being positive?Br Med J (Clin Res Ed). 1987;294(6581):1200–1202. doi:10.1136/bmj.294.6581.1200 [CrossRef]
- Uhlenhuth EH, Canter A, Neustadt JO, Payson HE. The symptomatic relief of anxiety with meprobamate, phenobarbital and placebo. Am J Psychiatry. 1959;115(10):905–910.
- Buckalew LW, Coffield KE. An investigation of drug expectancy as a function of capsule color and size and preparation form. J Clin Psychopharmacol. 1982;2(4):245–248. doi:10.1097/00004714-198208000-00003 [CrossRef]
- Schapira K, McClelland HA, Griffiths NR, Newell DJ. Study on the effects of tablet colour in the treatment of anxiety states. Br Med J. 1970;1(5707):446–449. doi:10.1136/bmj.2.5707.446 [CrossRef]
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- Moerman DE, Jonas WB. Deconstructing the placebo effect and finding the meaning response. Ann Intern Med. 2002;136(6):471–476. doi:10.7326/0003-4819-136-6-200203190-00011 [CrossRef]
- Branthwaite A, Cooper P. Analgesic effects of branding in treatment of headaches. Br Med J (Clin Res Ed). 1981;282(6276):1576–1578. doi:10.1136/bmj.282.6276.1576 [CrossRef]
- de Craen AJ, Tijssen JG, de Gans J, Kleijnen J. Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos. J Neurol. 2000;247(3):183–188. doi:10.1007/s004150050560 [CrossRef]
- Colloca L, Lopiano L, Lanotte M, Benedetti F. Overt versus covert treatment for pain, anxiety, and Parkinson’s disease. Lancet Neurol. 2004;3(11):679–684. doi:10.1016/S1474-4422(04)00908-1 [CrossRef]
- Moerman DE. Cultural variations in the placebo effect: ulcers, anxiety, and blood pressure. Med Anthropol Q. 2000;14(1):51–72. doi:10.1525/maq.2000.14.1.51 [CrossRef]
- Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 2008;336(7651):999–1003. doi:10.1136/bmj.39524.439618.25 [CrossRef]
- Moseley JB Jr., Wray NP, Kuykendall D, et al. Arthroscopic treatment of osteoarthritis of the knee: a prospective, randomized, placebo-controlled trial. Results of a pilot study. Am J Sports Med. 1996;24(1):28–34. doi:10.1177/036354659602400106 [CrossRef]
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Common Mediators of Placebo Effects
Expectancy: strengthened by verbal suggestions, desire for relief, reward, increased self-efficacy, anxiety reduction, and positive transference.
Therapeutic relationship: includes practitioner qualities, attitudes, styles of communication, treatment setting, patient’s experience of the relationship, and personality factors.
Efficacy is in the Mind of the Believer
Green: anxiety reducing
Expense: costlier is more effective8
Number of pills: more > fewer29
Capsules > tablets26
Brand vs. generic: unbranded placebo < branded placebo < generic aspirin < branded aspirin30
Route of administration: subcutaneous > oral31
Setting of administration: observed efficacy open > hidden32