the kinetics and dynamics of responses to placebo*

The kinetics and dynamics of responses to placebo

Murray Weiner, MD, and George J. Weiner, MD Cincinnati, Ohio, and Iowa City, Iowa

In a recent blinded drug study* in women in their first year of menopausal amenorrhea, the subjects understood they had a 75% chance of receiving a presumably active medication and a 25% chance of receiving a “dummy pill” (placebo) during a 4-week treatment period. The placebo group (n = 16) showed a statistically significant improvement in both the Kupperman score of menopausal symptoms and an elevation of blood estradiol levels (Fig. 1). Other hormone levels (es&one, follicle- stimulating hormone, and luteinizing hormone) did not change. Reanalysis of residual coded samples revealed no evidence of a coding error. It is conceiv- able but unlikely that an unrecognized substance in the placebo product was specifically active and responsible for the rise in estradiol levels. More likely, the study setting led to patient perceptions that resulted in both symptomatic and hormone level changes.

An alteration in subjective symptoms after treatment with a dummy pill is frequently observed and is generally accepted as a “placebo response” caused by the perceptions of the subject. However, changes in objectively measured hormone levels in response to placebo treatment raise interesting questions con- cerning the mechanisms of the placebo response and how they may relate to the mechanisms of active drug pharmacotherapy, including pharmacokinetics and pharmacodynamics.

This commentary is stimulated by the belief that a better understanding of the placebo response

*Personal communication of placebo data to M. Weiner, Febru- ary 1995. Published report pending.

From the Departments of Medicine, University of Cincinnati College of Medicine, Cincinnati, and the Iowa City Veterans Administration and the University of Iowa, Iowa City.

Supported in part by University Internal Medicine Associates Inc., Cincinnati, Ohio.

Received for publication Oct. 11, 1995; accepted April 22, 1996. Reprint requests: Murray Weiner, MD, Department of Medicine,

University of Cincinnati, Cincinnati, Ohio 4.5267-0508. Clin Pharmacol Ther 1996;60:247-54. 13/l/74339

can help improve the design and interpretation of drug studies and the management of therapeutics. It will review the characteristics of the placebo response, discuss the factors that can influence it, and evaluate relevant kinetic and dynamic mechanisms. It will also touch on the potential of modern molecular biology and genetics to assist in understanding the placebo effect. For classic and recent commentary on the history of the placebo concept, the reader is referred to earlier reviews.lw6

Characteristics and perceptions of the placebo The natural history of disease commonly involves

spontaneous remissions and cures that may be errone- ously attributed to a coincidental therapeutic measure. Textbooks of medicine routinely describe the usual course of events of illnesses over time. A major pur- pose for the design of placebo-controlled double-blind studies of the response to drugs or other therapeutic procedures is to distinguish spontaneous responses from the consequences of treatment.

When a placebo infusion precipitates seizures,7 those seizures are responses to placebo. Such responses should be distinguished from changes that occur coincidental to treatment. If there is no basis for suspecting an altered course as a result of treatment, the changes observed in a placebo-treated control group should not be considered placebo responses. It may confuse rather than help efforts to understand the nature of placebo-induced responses if one fails to distinguish spontaneous changes that occur in the course of time coincidental to treatment from a response that is truly the consequence of the procedure of treatment with placebo or an active drug.

The problem may be of particular concern when clinical impressions seem to support a popular therapeutic rationale. Years ago, concepts of the enzymatic clearing of inflammatory debris and reports of oral absorption of radiolabeled trypsin led to the use of oral trypsin derivatives to reduce

247

248 Weiner and Weiner CLINICAL PHARMACOLOGY & THERAPEUTICS

SEPTEMBER 1996

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KUPPERMAN SCORE Response to Placebo Treatment Days 1 through 28

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CHANGE IN HORMONE BLOOD LEVELS

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Fig. 1. Response of menopausal women to 28 days of placebo treatment. Upper graph, Percent of control Kupperman symptom score. Lower graph, Percent of control blood hormone levels. FSH, Follicle-stimulating hormone; LH, luteinizing hormone.

systemic inflammation, even though efficacy “. . . could not be determined from published data.“8 The presumed evidence of effective absorption has since been brought into question,’ and the absence of evidence of superiority over placebo suggests that the clinically observed reductions in inflammation reflected the natural course of events and was not a response to therapy.

The ceremony of taking a placebo, especially under conditions associated with a desire and expectation of relief, can initiate psychologic and biophysical events of therapeutic sign@ance. A perception, real or delu- sional, can trigger the generation or release of endogenous substances and a series of biochemical, physical, and emotional responses. Both the injec- tion of epinephrine and its release as a consequence

CLINICAL PHARhtA COLOGY &THERAPEUTICS VOLUME 60, NUMBER 3 Weiner and Weiner 249

of a perception result in a distinct and complex of the setting of a treatment improves the re- pattern recognizable as the adrenergic response that sponse. Although the investigator may be moti- prepares the individual for “fight or flight” accord- vated to reduce placebo effect to a minimum to ing to Cannon’s classic description of the action of help him or her to define the action of a drug, the the sympathetic nervous system and epinephrine.r’ practitioner may prefer to let placebo influences This pattern is probably the best recognized of contribute whatever they can to the patient’s wel- many l1 in which perceptions, including those asso- fare. ciated with placebo treatment, may trigger significant objective as well as subjective responses. The power of expectations,i’ the range and number of adverse events in healthy volunteers in response to placebo,i3 and the short-term improvement of chronic conditions after initiation of placebo thera- py14,15 all testify to the potential consequences of placebo.

Factors that influence the placebo response

An active placebo (i.e., one with effects that are a consequence of the drug entity but are basically irrele- vant to the condition being treated) may reinforce belief in the power of the medication, resulting in perceptions that help achieve the desired response. The active placebo is sometimes used in drug studies to help preserve the blinding of the investigation.16 Clin- ical experience suggests that it can result in a response greater than that achieved with inert dummy pills. The active placebo concept is unre- lated to the possible occurrence of adverse effects caused by excipients used in both drug and placebo formulations.17

Genetic and related physiologic variations. In an ongoing placebo-controlled double-blind study, the incidence of flushing in the placebo group is several times greater in women than in men.* Is this a gene-related phenomenon? Gender-related differences and other genetically based physiologic differences are not unusual encounters in drug studies.19-21 Much is known about the consequences of race-related, sex-related, and gene-related distur- bances on the response to drugs,22’23 but very little is known in regard to placebo responses.

Environmental variations. The number of life pattern factors that can influence responses to placebo are too numerous to review. In drug studies, entry criteria and stratification of subjects are used to help control the consequences of these variables. Of particular concern are components of the therapeutic setting listed below.

Placebo responses should not be dismissed as annoy- ing delusions that need to be prevented or eliminated when one is conducting a controlled study in search of objective truth. They should be accepted and evalu- ated as a component of the response to any form of therapeutic intervention. The range of influence of placebo extends from sociologic group phenomena” to chemical aspects of specific domains of well- characterized molecular species” and from the subject having subtle undetected responses to being literally scared to death or relieved of unbearable symptoms.

The doctor-patient interaction. The therapeutic response to placebo is strongly influenced by the doctor-patient interaction.2’24 When the therapist conveys an impression of limited confidence in his or her own prescription, the patient generally does not do as well as he or she would if the prescriber were enthusiastic.25

The physician who treats patients and the patient being treated are interested primarily in obtaining relief. The response itself, rather than an understanding of relevant therapeutic mechanisms, is the critical event in the eyes of the patient. When there is a clear diagnosis to explain the signs and symptoms and a treatment that can effect a cure, so much the better. If the cause, pathologic mech- anism, or cure is not fully known, as is so often the case, the goal is to control the manifestations of the disease without the introduction of new problems. The patient may benefit when the charisma

When a physical fitness program was repre- sented as specifically designed to improve self- esteem, a sequence of tests indicated that improvement was achieved. A control group, with whom self-esteem was not discussed, underwent the same program and achieved the same improvement in physical performance but with no effect on self-esteem.12

Analgesic studies often yield different average placebo response scores with different interviewers. In fact, with some clinical models, an observer with a sympathetic and optimistic nature can achieve such high placebo relief scores that there is little room to show a contribution over placebo by an analgesic with activity readily apparent from the data generated by other observers working with the

*Unreported interim analysis of a study in progress, 1995.

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same protocol.* In angina studies, high placebo success rates can also compromise the ability to evaluate a therapeutic agent, especially when the study numbers are relatively sma11.26

Perceptions injkenced by relevant pmious qveriences. The conditioned response is a well-recognized behavioral phenomenon.27 Previous long-term drug use can have a marked influence on responses to both drugs and placebo?8’29 The power of short- term drug treatment experience to influence response to placebo is shown by a study of three parallel groups of patients with pain treated first with one of three dose multiples of the analgesic propoxyphene, followed by a second treatment with placebo to all subjects.30 The three propoxyphene doses showed the expected dose-response relationship. However, the differences between the groups persisted in response to the second (placebo) treatment as well, a phenomenon attributed to the anticipation of analgesia based on previous experience.

Oncologists are acutely aware of the importance of suppressing nausea and vomiting in relation to the very first dose of chemotherapy, because that experience strongly influences the response to sub- sequent doses. Patients who come to associate treatment with severe nausea and vomiting often become nauseated by the mere idea of going to the clinic where treatment is administered. If the physiologic- biochemical pathways responsible for this phenomenon were known, they might be quite helpful in understanding placebo effects, which are in a sense the other side of the same coin.

Controlled studies have found that two placebo capsules can be more effective than one31 and that response may vary with the color of the medication.32 One can speculate that these results are consequences of earlier imprints.

Influence of the setting. Patient perceptions and expectations are very much a function of the therapeutic setting. Surroundings that breed confidence enhance response. A patient, mildly sedated preopera- tively, surgically draped, and prepared for saphenous ligation in a modern operating room, went through most of the procedure before it was realized that the planned local anesthetic infiltration had not been administered. In response to questioning, the patient, who thought he had been given a local anesthetic, indicated that he “felt them poking around” but was

*Bloomfield SS. Personal observation during analgesia studies at the University of Cincinnati, Department of Internal Medicine, Division of Clinical Pharmacology, 1990.

not in pain. The same patient winced and tensed when subjected to a simple antecubital venipuncture to get a routine blood sample.?

The cause-e$ect relationship between subjective and objective placebo responses. In the menopause study cited earlier, the significant improvement with placebo in the Kupperman symptom score was not surprising. However, the statistically significant elevation in estradiol blood levels (Fig. 1) was unexpected. Did a perception trigger a change in hormone levels associated with subjective responses such as with elevations in blood epinephrine produced by excitement? The cause-effect relationship is unclear. Although the rise in estradiol level as a percentage of the initial value was impressive and statistically significant, baseline postmenopausal levels were very low (average of 19 rig/L in this study) compared with the normal premenopausal range of 130 to 280 ng/L.33 Thus the estradiol change in nanograms per liter was relatively minor, and the role of the increased hormone level as the cause of changes in symptoms is in doubt.

The possibility of the mediation of subjective placebo responses through intermediate objective changes is seldom raised. Changes in endorphins in the fourth ventricles of animals have been studied to explain responses to acupuncture, but to date the effect of altered endogenous endorphin levels re- mains inconclusive.34

Placebo phenomena in relation to study design The critical importance of double-blind placebo-

controlled study leads the clinical investigator to seek every means possible to minimize or eliminate the placebo effect so as to maximize the discrimina- tion achieved by his or her study. However, he or she must guard against establishing criteria so rigid that the relevance of his or her conclusions to clinical use realities is compromised.

Ethical considerations are an overriding factor in study design. When the natural outcome of a disease is severe and uniform, it may not require concurrent placebo comparison to conclude that a highly effective agent works. Under such circumstances, use of historic controls may be valid. For example, when streptococcus viridans no longer grew in the blood cultures of patients with subacute bacterial endocar- ditis after intensive penicillin therapy, it was reason- able to conclude that the agent was effective without

TWeiner M. Personal observation, 1943.

CLINICAL PHARMA COLOGY & THERAPEUTICS VOLUME 60, NUMBER 3 Weiner and Weiner 25 1

a blinded, parallel, prospective, placebo-treated control group.

Should placebo responders be excluded from drug evaluation studies? The question implies that there is an identifiable subpopulation of persons who re- spond to placebo and others who do not. Although more suggestible persons might be expected to be more responsive to placebo, there has been very little success in improving the results of controlled studies of drugs by attempting to identify and eliminate placebo responders,35 a fact that testifies to our need for better information about the mechanisms responsible for responses to placebo.

The signs and symptoms of interest in a study often fluctuate widely over time, and subjects are likely to seek help when they are at their worst. Consequently, as a group they are destined to improve regardless of treatment. The concept of statistical regression36 ad- dresses this problem and deserves consideration.

The new attention paid to an old condition by a change in therapist or enrollment in a study may enhance the likelihood of a stronger placebo response. In most studies of chronic angina, all groups, including placebo groups, show improvement during the first week15; therefore longer periods of observation may be necessary to distinguish an effective drug from placebo.

Patients with mild reactive depression showed a marked improvement in mood after 10 days of placebo pill treatment.37 They were then divided into continuing placebo treatment versus no treatment groups for the next 6 weeks. There was no difference in the rate of relapse. This experience illustrates that short- and long-term placebo responses may differ, and it brings into question the value of placebo treatment during experimental washout periods.

New attention is often accompanied by new motivation that can induce disease-altering behavioral changes. To help control this variable, studies may be designed with an initial placebo lead-in period for all subjects?

An effective anorexiant may fail to show efficacy over placebo in the first phase of a study if it is initiated with a great deal of attention to dietary instructions and encouragement. This occurs because patients strongly motivated to adhere to their diets will achieve weight loss whether or not their appetites are weakened.*

Although the value of an anorexiant may become

*Weiner M. Unpublished observations during anorexic drug studies, 1988.

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Fig. 2. Time-effect curves for la&se, 600 mg aspirin, 32 Fig. 2. Time-effect curves for la&se, 600 mg aspirin, 32 mg codeine, and a combination of 600 mg aspirin and 32 mg codeine, and a combination of 600 mg aspirin and 32 mg codeine. Changes in pain intensity (ordinate) are plot- mg codeine. Changes in pain intensity (ordinate) are plotted against time in hours {absciha). Eleven patients with ted against time in hours {absciha). Eleven patients with pain due to cancer received a total of 20 oral doses of each pain due to cancer received a total of 20 oral doses of each medication administered in random order. (From Houde medication administered in random order. (From Houde RW, Wallenstein SL, Beaver WT. International encyclo- RW, Wallenstein SL, Beaver WT. International encyclopaedia of pharmacology and therapeutics; vol 1, clinical paedia of pharmacology and therapeutics; vol 1, clinical pharmacology. Oxford: Pergamon Press, 1966:88. Used pharmacology. Oxford: Pergamon Press, 1966:88. Used with permission.) with permission.)

more apparent after motivation starts to slip, both placebo-treated groups and active drug-treated groups tend to show reduced responses with time.i4 If a placebo-controlled anorexiant study of weight loss is initiated with little fanfare or new dietary instruction or if it is begun after motivation to control diet has been exhausted, it is more likely that a real difference in weight loss will be shown between an effective anorexiant and a placebo in the first week of the study.

In spite of numerous objective responses to placebo summarized decades ago12 and the well-known patterns of hormonal response to chronic stress3’ placebo controls are sometimes considered to be unnecessary when an objective parameter, such as a blood level, is the critical variant in the study. Inves- tigators are often hesitant to accept the possibility of objective changes in response to placebo. Such changes cause concern that there was a mix-up in coding or recording that puts into question the va- lidity of all aspects of the study. If the bulk of the

252 Weiner and Weiner CLINICAL PHARMA COLOGY & THEBAPEUTICS

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Table I. Pharmacodynamic factors that may be altered by placebo-induced changes Factor Example Reference

Metabolic changes altering allosteric sites

Hormonal changes altering sensitivity to other stimuli

Engaging one receptor can influence response to other receptors

Changing transmembrane structures can alter signaling

Changing intracellular signaling pathways

pH and 2,3 DPG changes oxygen binding to hemoglobin

Changes in steroid concentration have an impact on response of immune system

Response to engagement of T-cell receptor depends on status of costimulation via CD28

Change in receptor-linked G protein alters response to agonist

Weinerl’

Selye3’

Jeukins4’

Hirata et aL4’

Small changes in signaling protein con- centrations can modify homodimer/ heterodimer ratios of Bcl-2, B&x, and other factors involved in programmed cell death

Korsmeye?’

2,3 DPG, 2,3-diphosphoglycerate.

data are consistent with expectations, investigators are tempted to discard the disturbing objective parameter placebo results as the consequence of a laboratory handling or technical error rather than to trash the entire study. In this way the skeptical reception that the unexplained placebo data might have received can be avoided. As a consequence, objective changes after placebo administration are probably underreported to a degree difficult to as- sess.

Well-conducted placebo-controlled double-blind studies do not guarantee valid conclusions if the investigator’s approach to the data is faulty. For example, a recent double-blind study compared the side effects of two preparations in equal milligram doses instead of equieffective doses.39 As a result, the sound data in this nicely designed and executed double-blind study led to a quite inappropriate con- clusion4’

Pharmacokinetics In a literal sense, there can be no such thing as the

pharmacokinetics of placebo because there is noth- ing to be absorbed, distributed, metabolized, ex- creted, or sought at specific tissue sites. However, there are several considerations that should be reviewed before pharmacokinetics is completely dismissed in regard to placebo.

First, placebo response often shows quantifiable characteristics that can be described by use of calculations usually applied to indicate pharmacokinetic characteristics of an active drug.41 Thus the time and intensity of peak response and rate of fall-off of effect, which frequently correspond to drug blood level patterns, are observable after

placebo. For some clinical models, numbers generated from placebo response data, such as those shown in Fig. 2, can be used to calculate pharmacokinetic-based parameters such as time and intensity of peak (tmaX and C,,,), rate of fall (t,,,), and area under the curve (AUC) generally assumed to represent overall exposure to the drug. AUC42 or slope of response score plotted against time43 can yield quantitative values for the placebo responses.

Second, placebo-generated perceptions can result in the production or release of endogenous active materials that may indeed have a kinetic fate anal- ogous to that of administered active exogenous drugs.

Third, an important aspect of pharmacokinetics is enterohepatic circulation, which involves the biliary or mucosal secretion of circulating drugs, hormones, or metabolites with reabsorption in an unchanged or altered form.44 The resulting complex patterns of blood levels of a number of substances may be influenced by gastrointestinal motility and pH changes induced by perceptions such as those associated with placebo treatment.45

Finally, the local fate of active drugs and perhaps active endogenous agents within the brain can be influenced by local blood flow and rate of agonist turnover (local synthesis, release, reuptake, and metabolic conversion). A plan of “activity directed drug disposition” has been proposed to help enhance drug delivery to a desired site by taking measures to alter local blood flow and endogenous agonist turnover rate at that site.46 Such perception sensitive kinetic factors could be influenced by placebo.

CLINICAL PHARMA COLOGY & THERAPEUTICS VOLUME 60, NUMBER 3

Pharmacodynamics Pharmacodynamics is defined as the action of

drugs in living organisms.47 It is the sequence of events flowing from agent-receptor interactions that alter some entity or function, ultimately observed as a clinical response. It is often studied in isolated organ models or in vitro at the cellular and subcel- lular level. Such models are rarely applicable to the study of placebo. Nevertheless, placebo consequences may induce modifications in response to drugs or endogenous agonists as a result of pharmacodynamic modifications. Some mechanisms that may be sensitive to such alterations are outlined briefly in Table I.

The mechanisms reviewed in Table I and the models designed for their investigation are usually based on a proposed theory of pharmacodynamic action. Such models can hardly take into account changes that may be triggered by placebo mechanisms in the clinical setting. If duplication of such models under different “standard” conditions yields nonidentical results, it can be surmised that there may be opportunities for placebo-induced influences in patients receiving treatment.

Ultimately one must deal with the complex condition of a patient with a particular disturbance, status, and background. Although it is apparent that the dynamics of responses to placebo is frustratingly complex and difficult to investigate, it is essential to recognize the possibility and seek to apply modern concepts and technology to gain a better understanding of the mechanisms involved.

Conclusions The word placebo generally carries a negative con-

notation of being the tool of dishonest therapists and gullible uncritical responders. A more appropriate modern connotation relates it to the influence of the milieu in which therapeutic measures are taken on the response to those measures. If the treatment has no intrinsic capacity to cause a response, the occurrence of a response that is not simply coincidental to therapy is a placebo effect. It is a very common, often unavoid- able, and integral component of therapeutics and is in itself neither false nor dishonest. When objective changes in response to placebo are unexpected and not readily understood, they are likely to be dismissed and go unreported. Placebo and active drug effects are often intertwined and not mutually exclusive. Each can significantly influence the other. The value of efforts to study and quantify the placebo response lies not only in the use of placebo in investigations aimed at deter-

Weiner and Weiner 253

mining the “true” response to a therapeutic procedure but also for a better understanding and greater therapeutic success in the clinical use of active drugs. The interactions between a therapist and a subject can have a profound effect on patient perceptions and consequently the response to treatment. There is need for better understanding of the influences of perceptions and methods of manipulating perceptions so as to optimize the results of therapy and the design of controlled studies that are relevant to the real world of clinical treatment. However, the dedicated scientific therapist has no need to adopt insincere techniques to enhance the placebo effect. His or her credibility as a medical scientist serves him or her well in this regard.

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the kinetics and dynamics of responses to placebo*

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