Do “placebo responders” exist?

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Abstract

The placebo effect has been the subject of much controversy. For a scientific investigation of placebo effects to advance it is important to establish whether a placebo response in any particular illness is reliable — i.e., if there is a response to a single placebo administration there will also be a placebo response to the repeated administration of a similar placebo in similar conditions. A positive answer would allow more sophisticated clinical trial designs and more precise basic research experiments on the placebo effect. This article reviews experiments that used multiple administrations of placebo to answer the question “do reliable placebo responders exist?” This paper also examines the evidence for the existence of a consistent placebo responder, i.e. a person who responds to placebo in one situation will respond in another condition or using a different type of placebo ritual. Much of the existing evidence for these two questions was performed before 1967. This early evidence is contradictory, methodologically weak and is sufficiently old to be considered medical history. Since 1969, at least eight experiments exposed asthma patients to multiple administrations of placebo given with deceptive suggestions that the “treatment” was an active medication. While the results of this research are not unequivocal, and may not be equivalent to non-deceptive conditions, this line of inquiry suggests that if a reliable and consistent placebo response exists it could be detected within this population. Finally, this paper proposes one model to rigorously investigate the stability of placebo responses.

Introduction

Until about 1955, a placebo was an innocuous substance – a “pious fraud” – given to manage difficult patients [1], [2]. With the rise of the placebo-controlled randomized controlled trial (RCT), it became evident that the placebo arm of trials often produced significant clinical changes [3]. Yet placebo effects remain poorly understood. Recently, sophisticated laboratory studies on very short-term placebo treatment have revealed quantifiable changes in neurotransmitters, hormones, immune regulators and regionally specific brain activity that could influence peripheral disease processes through plausible physiological mechanisms [4], [5], [6], [7], [8], [9]. Whether and how these short-term laboratory induced placebo effects apply to research and clinical outcomes over time remains unclear [10], [11].

A key challenge for placebo studies is the absence of knowledge concerning whether a placebo effect demonstrated in any trial or experiment is replicable. Within any particular medical condition, are there people who respond more or less reliably when administered a placebo treatment? Are we studying something that is stable? Answers to these questions and the detection and characterization of any such individuals would potentially allow for more efficient RCT designs, a more “personalized” approach in clinical care and more definitive placebo mechanism studies. For example, accurate identification of placebo responders might allow more efficient entry criteria in RCTs and allowed a more precise selection of medications in clinical practice. In basic science research, if people respond inconsistently to a placebo intervention the search for genetic, immunological, or neurological mediators of placebo responses may be extremely difficult and require different modeling assumptions [12]. Advances on all these fronts, would benefit from a better understanding of the stability of a placebo response.

For early pioneers of the RCT, distinguishing placebo responders from non-responders was a major issue [13]. Researchers worried that genuine drug efficacy could be obscured in an experiment with a large number of placebo responders or the optimal dosage of a medication could easily be miscalculated [14]. Then, as now, high placebo response rates in RCTs threatened the detection of an active pharmacological effect [15], [16], [17], [18]. The most common method of attempting to detect placebo responders was a retrospective strategy in which baseline demographic, psychosocial, personality, and behavioral variables were correlated with responses in the placebo arm of RCTs [19]. Such analyses continue to this day [20]. While these efforts have been extensive, the conclusion of the most recent reviews of these efforts have been similar: “many variables were identified as being associated with placebo effects, but there was little or no agreement [between trials] about which variables contributed to…the placebo reaction.... [Associations] could not be replicated and they simply disappeared into the wastebasket of history, never to be heard from again.”[21] (cf. [22], [23]) These reviews echoed the conclusion of reviews from an earlier era. [24], [25], [26], [27].

The failure of these retrospective analyses is likely due to inherent limitations in methodology. One weakness was the inability of these studies to clearly document that the phenomena they measured were, in fact, placebo responses beyond the effects of natural history and regression to the mean. An additional natural history control to distinguish a genuine placebo effect was generally absent. What was called a “placebo effect” could have easily been a mistaken label for spontaneous remission and natural variability, Hawthorne effect, measurement drift or the response to nursing care, bed rest, or other common co-interventions [28]. Ultimately, little clarity has been gleaned with this methodology. Furthermore, by considering a placebo administration episode as a cycle of baseline assessment, placebo administration, response, and re-assessment, these retrospective studies rely on a single placebo administration from which a subject's placebo reactivity is inferred. One researcher called making such an inference about a placebo response being more than chance as “near indefensible” [26].

Common forms of statistical representation can also contribute to confusion concerning placebo responses. For example, if 50% of patients on placebo improve, the typical interpretation is that 50% of the patients are placebo responders. Although at first glance this interpretation seems to be perfectly reasonable, Senn has pointed out there are several alternative interpretations [12]. It is possible that 100% of patients respond to placebo 50% of the time implying that all patients are partial placebo responders. If this interpretation were true, there would be no way to distinguish between placebo responders and non-responders. It would only be a matter of chance as to who ended up being identified as a responder in any single trial. This interpretation would explain why it has been so difficult to identify any replicable characteristics that separate placebo responders from non-responders. An additional typical assumption is that the 50% of patients who responded to placebo will reliably respond to the placebo, and that, therefore, they must differ in some way from non-responders. Patients who respond to a single placebo administration are usually labeled “placebo responders,” and unfortunately, it is easy to reify this label and assume that they would respond reliably. Another possible interpretation is that some patients may be reliable placebo responders, others may be partial responders, and some may never respond to placebo. The only way to determine which interpretation of placebo responses is correct is to run patients through multiple placebo administrations. This paper will review the few studies that prospectively studied the existence of placebo responders with repeated administrations of placebo. Some of these experiments were concerned with the reliability of placebo response: if there is a response to a placebo administration for a symptom or condition will there be a placebo response to the repeated administration of a similar placebo under similar conditions? Other experiments studied the consistency of response: if there is a response to a single placebo administration will there be a response to a different placebo or therapeutic ritual? After examining these experiments, we will present one model for the future investigation of placebo responders.

Section snippets

Lasagna and colleagues (1954) [14]

To our knowledge, the placebo pioneer team of Lasagna, Mosteller and Beecher at Harvard Medical School performed the first experiment to detect placebo reactors using multiple administration of placebo therapy on the same patient population. In this experiment, 93 patients with severe post-operative pain repeatedly received placebo or morphine in alternating order. Medication or placebo was considered to have produced relief when the patient indicated significant relief of pain (“over 50%”) at

Experiments on placebo responses in asthma patients

Between 1968 and 2003, multiple experiments were performed to test the effects of “suggestion” on asthma patients [35]. Usually, placebo inhalator was given to patients who were deceptively “told” that the placebo was either a bronchodilator or bronchoconstrictor (e.g., placebo allergen). Rooted in a psychosomatic research agenda, these experiments were not designed to test the stability of placebo response. Nonetheless, a close examination of these experiments reveals at least eight

An asthma model for investigating the stability of placebo response

In an effort to investigate placebo responders, our team has recently undertaken an experiment that we hope will provide more reliable evidence of the existence or non-existence of such responders or at least valuable preliminary data. Earlier asthma experiments suggest a reasonable likelihood for finding placebo reactors if they exist. Chronic asthma patients also have the characteristic that withholding regular medications the evening of the day before experimental sessions would induce

Conclusion

Previous research on the reliability and consistency of placebo response is contradictory and flawed. Based on an examination of previous experiments of asthma, our team proposes an experiment to further investigate the possibility that reliable and consistent placebo responders exist. Our experimental design addresses many of the shortcomings of previous placebo responder experiments.

Acknowledgements

This publication was made possible by Grant Number 1 R21 AT002793-01A1, 1 R21 AT002564 and 1 K24 AT004095 from the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCCAM or the NIH.

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