The Placebo Response: Recent Research and Implications for Family Medicine

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Original Research

The Placebo Response: Recent Research and Implications for Family Medicine

J Fam Pract. 2000 July;49(7):649-654

References

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Attention has recently turned to meta-analyses of the placebo response.^9,13,14 One sophisticated analysis of placebo-controlled studies with more than 2 arms suggests that so-called “nonspecific” effects may be substantial and may be either synergistic or antagonistic toward “specific” effects, so the merely “additive” model of the placebo and drug effects, implicit in the design of most randomized controlled trials, is overly simplistic.¹⁵

Hypothetical Models

According to a meaning model,¹⁶ a positive placebo response is most likely to occur when the meaning of the illness experience is altered in a positive direction. A positive change in meaning occurs when one or more of 3 things happens: The patient feels listened to and receives a satisfactory, coherent explanation of his illness; the patient feels care and concern from those around him; and the patient feels an enhanced sense of mastery and control over his symptoms. Because the meaning that we attach to events in our lives often hinges on the stories we construct about those events, this model helps explain the importance of narrative in medicine.^17,18

Support for this model comes from several directions. In a psychology laboratory, a group of subjects told about the potentially healthful effects of brief hand immersion in ice water had better pain tolerance than a group briefed on the dangers of cold immersion, and both groups were significantly different from control subjects given a neutral message.¹⁹ In clinical research, the informed consent process is often thwarted by the “therapeutic misconception,” the tendency of subjects to believe that they are getting medical care aimed at their personal medical problems despite being told that their treatment is selected by the research protocol.²⁰ The therapeutic misconception might enhance the placebo response and make it more difficult to show that an active drug is superior to placebo.

Placebo-Prone Personalities

Much of the early literature on the placebo response was devoted to identifying a “placebo personality type,” in the vain hope that such subjects could be eliminated from clinical trials so as not to confuse the results with placebo responses. In general, this early literature^21,22 concluded that no such personality type exists and that the placebo response is more a contextual situational phenomenon than an enduring personality trait.

One important exception to this general conclusion is highlighted in a superb recent review of the placebo literature. Fisher and Greenberg²³ argue that the “acquiescent” personality type is more likely to experience positive placebo responses. At first misunderstood as passivity, the label “acquiescent” is now better understood as an active coping mechanism. This type of person deals with adversity by developing positive relationships with others and using them as a healing resource. This suggests the importance of continuity of care and effective interpersonal relationships in producing positive placebo responses as part of daily practice.

Theories of Placebo Action

Experimental data currently support 2 general theories about the placebo response: expectancy and conditioning.^22,24 The first proposes that bodily changes occur to the extent that the subject expects them to; the second, that bodily changes occur when the subject is exposed to a stimulus that has been linked in the past to active processes that produce the change.

A classic study of expectancy²⁵ showed subjects unable to distinguish the pharmacologic properties of amphetamines and chloral hydrate when they had no expectancy cues for the drugs they were receiving. A recent study of conditioning²⁶ showed that young asthmatics, exposed over time to a vanilla aroma at the same time as they used their metered dose inhalers, demonstrated objective bronchodilation when later exposed only to the vanilla.

We may view these theories, taken in conjunction with the meaning model, as complementary not competing. Conditioning theory may explain how the past experiences of the patient affect the meaning attached to present events, while expectancy focuses on how the patient’s thoughts of the future may influence therapeutic outcomes.

Biochemical Mediators

Neither expectancy nor conditioning theory explains the process by which the altered meaning in the patient’s mind causes a change in bodily status. The complete answer to the neuroanatomy and biochemistry of the placebo response is unknown. The most interesting research has focused on 3 pathways: endorphins, cathecholamines and cortisol, and psychoneuroimmunology. All are capable of altering bodily symptoms, and all are known to be connected intimately with the individual’s emotional and cognitive state.

An elegant, recent, 12-armed trial conducted in a psychology laboratory²⁷ compared 2 aspects of placebo response to pain: expectancy versus conditioning, and conditioning with morphine versus conditioning with ketorolac. The results showed that placebo analgesic effects produced by expectancy could be reversed by naloxone, suggesting that these might be endorphin mediated. Similarly, placebo conditioning with morphine could be reversed by naloxone, but the placebo response was not naloxone-reversible when ketorolac was used as the initial stimulus. The authors concluded that the biochemical pathway for placebo conditioning might depend on the biochemical pathway activated by the active drug.