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Commercial Features of Placebo and Therapeutic Efficacy

In response to Dr Browning, I did not lay the problems
of general surgery “at the feet of primary care.” Having been
involved in an effort to undo the flawed sustainable growth
rate system for the past decade, I know that the system is
broken. In a rational world, specialties would unite to cor-
rect this flawed system, which seems cynically designed to
pit specialties against each other.
The calculations for physician compensation used in
the cited study of internal medicine reimbursement
off in 2004 while the increases in evaluation and manage-
ment codes took place in 2004 through 2007. For
example, evaluation and management codes increased in
work relative value units from 2006 to 2007 (code 99213:
increase from 0.67 to 0.92 [37%]; code 99214: 1.10 to
1.42 [29%]; and code 99215: 1.77 to 2.00 [12.9%]). Fur-
thermore, this article has been rebutted.
The primary
care–specialty income gap has largely been corrected, at
an estimated cost of $4 billion.
I appreciate the enthusiasm of Dr Maa and colleagues
for the surgical hospitalist, particularly in emergency and
trauma care. However, I do not believe this is the answer
to the shortage of general surgeons, who not only do
emergency and trauma care but often perform endoscopy
and other general surgical operations in critical access
Philosophically, I have difficulty with medical or surgi-
cal hospitalists. My objection to the medical hospitalist
system is that patients may perceive that they are being
abandoned by their primary care physician at a time of
their most dire need—when they are sufficiently ill to
require hospitalization. I would hope that this sense of
abandonment is not present in a surgical hospitalist sys-
tem. When we train “physicians who operate,” we try to
instill judgment about the need for surgery. But if opera-
tion is required, the operator must be thoroughly compe-
tent. I believe that such decisions are more informed
when the physician/surgeon is familiar with the patient.
The surgical hospitalist system may aid trauma and emer-
gency care in urban centers but will not solve the access
problem in small rural hospitals.
Josef E. Fischer, MD
Department of Surgery
Harvard Medical School
Boston, Massachusetts
Financial Disclosures: None reported.
1. Zuckerman R, Doty B, Gold M, et al. General surgery programs in small rural
New York state hospitals. J Rural Health. 2006;22(4):339-342.
2. Smart DR, ed. Physician Characteristics and Distribution in the US, 2007. Chi-
cago, IL: American Medical Association; 2007.
3. Bodenheimer T, Berenson R, Rudolf P. The primary care-specialty income gap:
why it matters. Ann Intern Med. 2007;146(4):301-306.
4. Rich WL III. The primary care-specialty income gap. Ann Intern Med. 2007;
5. Centers for Medicare & Medicaid Services (CMS). Medicare program: revi-
sions to payment policies, five-year review of work relative value units, changes
to the practice expense methodology under the physician fee schedule, and other
changes to payment under part B. Fed Regist. 2006;71(231):69623-70251.
Commercial Features of Placebo
and Therapeutic Efficacy
To the Editor: It is possible that the therapeutic efficacy of
medications is affected by commercial features such as lower
prices. Because such features influence patients’ expecta-
they may play an unrecognized therapeutic role by
influencing the efficacy of medical therapies, especially in
conditions associated with strong placebo responses.
investigate this possibility, we studied the effect of price on
analgesic response to placebo pills.
Methods. In 2006 we recruited 82 healthy paid volunteers
in Boston, Massachusetts, using an online advertisement. Each
participant was informed by brochur eabout a (purported) new
opioid analgesic approved by the Food and Drug Administra-
tion; it was described as similar to codeine with faster onset time,
but it was actually a placebo pill. After randomization, half of
the participants were informed that the drug had a regularprice
of $2.50 per pill and half that the price had been discounted to
$0.10 per pill (no reason for the discount was mentioned). All
participants received identical placebo pills and were paid $30.
Participants were blinded to the study purpose, and research-
ers were blinded to groupassignment. The study was approved
by the Massachusetts Institute of Technology institutional re-
view board, and all participants providedwritten informed con-
sent and were debriefed after the study.
The protocol followed an established approach for studying
Electrical shocks to the wrist were calibrated to each par -
ticipant’s pain tolerance. After calibration, participants received
the test shocks, rating the pain on a computerized visual ana-
log scale anchored by the labels “no pain at all” and “the worst
pain imaginable.” Participants received all possible shocks in
2.5-V increments between 0 V and their calibrated tolerance.
Stimulation at each intensity level was carried out twice for each
participant (before and after taking the pill), and the change
in reaction to the stimulation was assessed. V isual analog scale
ratings were converted to a 100-point scale, the postpill score
for each voltage was subtracted from the prepill score, and the
mean of these differences was calculated for each participant.
The per centage of participants experiencing a mean score re-
duction vs increase was compared between the 2 groups using
a 2-tailed
test. Because stronger pain may be associated with
stronger placebo responses,
we also compared r esults for the
50% most painful shocks for each participant. In addition, mean
differ ences at each voltage between the 2 groupswer e compar ed
overall with a sign test and individually with F tests. A P value
of .05 was considered statistically significant. Analyses were per-
formed using SPSS version 15 (SPSS Inc, Chicago, Illinois).
Results. Patient characteristics are shown in the T
the regular-price group, 85.4% (95% confidence interval [CI],
74.6%-96.2%) of the participants experienced a mean pain re-
duction after taking the pill, vs 61.0% (95% CI, 46.1%-75.9%)
in the low-price (discounted) group (P =.02). Similar results
1016 JAMA, March 5, 2008—Vol 299, No. 9 (Reprinted) ©2008 American Medical Association. All rights reserved.
at INSEAD, on March 4, 2008 www.jama.comDownloaded from
occurredwhen analyzing only the 50% most painful shocks for
each participant (80.5% [95% CI, 68.3%-92.6%] vs 56.1% [95%
CI, 40.9%-71.3%], respectively; P =.03).
Considering all voltages tested, pain reduction was greater
for the regular-price pill (P .001). In addition, for 26 of
29 intensities (from 10 to 80 V), mean pain reduction was
greater for the regular-price pill (F
Comment. These results are consistent with described phe-
nomena of commercialvariables affectingquality expectations
and expectations influencing therapeutic efficacy.
Placebo re-
sponses to commer cial featureshavemany potential clinical im-
plications. For example, they may help explain the popularity
of high-cost medical therapies (eg, cyclooxygenase 2 inhibitors)
over inexpensive, widely available alternatives (eg, over-the-
counter nonsteroidalanti-inflammatory drugs) and why patients
switchingfr om branded medicationsmayr eportthattheir generic
equivalents are less effective. Studies of real-worldeffectiveness
may be more generalizable if they reflect how medications are
sold in addition to how they are formulated. Furthermore, cli-
nicians may be able to harness quality cues in beneficial ways,
for example, by de-emphasizing potentially deleterious com-
mercial factors (eg, low-priced, generic).
These findings need to be replicated in broader popula-
tions and clinical settings to better understand how commu-
nicating quality cues with patient populations can maximize
treatment benefits and patient satisfaction.
Rebecca L. Waber, BS
Massachusetts Institute of Technology
Cambridge, Massachusetts
Baba Shiv, PhD
Stanford University
Stanford, California
Ziv Carmon, PhD
Dan Ariely, PhD
Massachusetts Institute of Technology
Author Contributions: Dr Ariely had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Waber, Shiv, Carmon, Ariely.
Acquisition of data: Waber.
Analysis and interpretation of data: Waber, Ariely.
Drafting of the manuscript: Waber, Shiv, Ariely.
Critical revision of the manuscript for important intellectual content: Waber, Shiv,
Carmon, Ariely.
Statistical analysis: Waber, Ariely.
Obtained funding: Ariely.
Administrative, technical, or material support: Waber.
Study supervision: Ariely.
Financial Disclosures: None reported.
Funding/Support: This study was funded by the Massachusetts Instituteof Technology.
Role of the Sponsor: The sponsor had no role in the design or conduct of the study;
the collection, management, analysis, or interpretation of data; or the preparation,
review, or approval of the manuscript.
Additional Contributions: Taya Leary, MS, Tom Pernikoff, BS, and John Keefe, BS, all
with the Massachusetts Institute of Technology at the time of this study, provided as-
sistance in datacollection. Mr Keefe receivedcompensation for thisrole. Andrew Lippman,
PhD, Massachusetts Instituteof Technology, provided logisticalsupport and MarkVangel,
PhD, Massachusetts General Hospital, provided statistical assistance. Neither received
compensation for these roles.
1. Rao AR, Monroe KB. The effect of price, brand name, and store name on buy-
ers’ perceptions of product quality. J Marketing Res. 1989;26(3):351-357.
2. Benedetti F. How the doctor’s words affect the patient’s brain. Eval Health Prof.
3. Koshi EB, Short CA. Placebo theory and its implications for research and clini-
cal practice. Pain Pract. 2007;7(1):4-20.
4. Berns GS, Chappelow MC, Zink CF, Pagnoni G, Martin-Skurski ME. Neurobio-
logical substrates of dread. Science. 2006;312(5774):754-758.
5. Price DD, Fields HL. The contribution of desire and expectation to placebo an-
algesia: implications for new research strategies. In: Harrington A, ed. The Placebo
Effect: An Interdisciplinary Exploration. Cambridge, Massachusetts: Harvard Uni-
versity Press; 1999:118-119.
6. Gracely RH, Dubner R, Deeter WR, Wolskee PJ. Clinicians’ expectations influ-
ence placebo analgesia. Lancet. 1985;1(8419):43.
Table. Comparison of Participants Assigned to Regular-Price Placebo
vs Low-Price (Discounted) Placebo
Regular Price
(n = 41)
Low Price
(n = 41)
Women, No. (%) 27 (65.9) 24 (58.5) .50
Age, mean (SD), y 30.9 (12.4) 30.0 (11.4) .74
Calibrated maximum tolerance,
mean (SD), V
51.8 (18.7) 54.9 (23.3) .50
Shocks received, No. (SD) 18.2 (7.2) 18.6 (9.1) .80
Change in pain scores
All shocks,
No. (%) [95% CI]
Pain reduction 35 (85.4)
25 (61.0)
Pain increase 6 (14.6)
16 (39.0)
Highest-intensity shocks only,
No. (%) [95% CI]
Pain reduction 33 (80.5)
23 (56.1)
Pain increase 8 (19.5)
18 (43.9)
Abbreviation: CI, confidence interval.
Comparison of participants experiencing a mean reduction in pain after vs before the
placebo pill was administered (visual analog scale point reduction between 0.01 and
48.4) and those experiencing a mean increase in pain (visual analog scale point in-
crease between 0 and 29.2).
Highest 50% of shocks by intensity.
Figure. Pain Ratings by Voltage Intensity
Regular price
Low price
Shock Intensity, V
Mean Difference
Placebo price
15 20 25 30 35 40 45 50 55 60 65 70 75 80
41 41 40 37 31 27 23 21 20 18 14 12 9 8
41 41 41 40 38 31 29 27 24 19 17 11 7 5 4
Mean difference in pain ratings, after vs before placebo, by voltage intensity. Higher
value indicates greater pain reduction. The table depicts the intensity of the shocks
and the number of observations in the regular-price and low-price conditions. P
value is less than .05 for the shock intensities 27.5 V through 30.0 V, 35.0 V through
75.0 V, and 80.0 V.
©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, March 5, 2008—Vol 299, No. 9 1017
at INSEAD, on March 4, 2008 www.jama.comDownloaded from
... Placebo analgesia is a well-documented phenomenon in which a person reports that pain weakens when she believes that an analgesic agent has been administered, even if only a placebo was given (e.g., Amanzio et al., 2001;Bingel et al., 2011;Waber et al., 2008) 2 . It is proposed that the analgesic effect occurs due to the function of descending pathways, which modulate spinal activity by release of endogenous opioids (see Atlas and Wager, 2012;Heinricher andFields, 2013, andWiech, 2016 for a review). ...
... This claim is also strengthened by the fact that the way in which beliefs and expectations relevant for placebo analgesia are processed is heavily influenced by background propositional knowledge and other cognitive information. For instance, the occurrence and strength of placebo analgesia is influenced by observing another person receiving similar treatment (Bieniek and Bąbel, 2022;Colloca and Benedetti, 2009), the presence of a medical setting (Bingel et al., 2011), and the perceived quality of analgesic substance (Waber et al., 2008). While the presence of a cognitive penetration of sensory systems is controversial, it is common for mechanisms of central cognition to influence each other. ...
... Nevertheless, it is unlikely that EBMs play only a passive role. The beliefs and expectations relevant for placebo analgesia are not somehow passively transmitted, but are generated relying on a variety of information regarding other beliefs about the current situation and a background knowledge about painkillers and the medical setting (e.g., Bieniek and Bąbel, 2022;Colloca and Benedetti, 2009;Waber et al., 2008). In fact, the role of EBMs is likely to be far less passive than that of nociceptive mechanisms providing input to the spinal pain gates. ...
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Discussions concerning the modularity of the pain system have been focused on questions regarding the cognitive penetrability of pain mechanisms. It has been claimed that phenomena such as placebo analgesia demonstrate that the pain system is cognitively penetrated; therefore, it is not encapsulated from central cognition. However, important arguments have been formulated which aim to show that cognitive penetrability does not in fact entail a lack of modularity of the pain system. This paper offers an alternative way to reject the modularity of the pain system, which is independent from, but consistent with, the presence of cognitive penetration. It is proposed that, given the current knowledge regarding the functioning and the structure of the pain system, there are good reasons to accept that certain central cognitive mechanisms are part of the pain system. It is argued that such a 'cognitive constitution' of the pain system entails that the pain system is not modular.
... Finally, low-cost SSRIs are covered by insurance and there is no cost to the patient, which argues against a placebo effect. 53 However, the possibility of a placebo effect can only be completely ruled out by an RCT. but perhaps also of a group of initially healthy people who were fully employed. ...
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After Covid-19 infection, 12.5% develops post-Covid-syndrome (PCS). Symptoms indicate numerous affected organ systems. After a year, chronic fatigue, dysautonomia and neurological and neuropsychiatric complaints predominate. In this study, 95 PCS patients were treated with selective serotonin reuptake inhibitors (SSRIs). This study used an exploratory questionnaire and found that two-thirds of patients had a reasonably good to strong response on SSRIs, over a quarter of patients had moderate response, while 10% reported no response. Overall, patients experienced substantial improved well-being. Brainfog and sensory overload decreased most, followed by chronic fatigue and dysautonomia. Outcomes were measured with three different measures that correlated strongly with each other. The response to SSRIs in PCS conditions was explained by seven possible neurobiological mechanisms based on recent literature on PCS integrated with already existing knowledge. Important for understanding these mechanisms is the underlying biochemical interaction between various neurotransmitter systems and parts of the immune system, and their dysregulation in PCS. The main link appears to be with the metabolic kynurenine pathway (KP) which interacts extensively with the immune system. The KP uses the same precursor as serotonin: tryptophan. The KP is overactive in PCS which maintains inflammation and which causes a lack of tryptophan. Finally, potential avenues for future research to advance this line of clinical research are discussed.
... Finally, low-cost SSRIs are covered by insurance and there is no cost to the patient, which argues against a placebo effect. 32 However, the possibility of a placebo effect can only be completely ruled out by an RCT. ...
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After Covid-19 infection, 12.5% develop a post-Covid-syndrome. Symptoms affect numerous organ systems, but after one year they are mainly neurological and neuropsychiatric in nature. There is evidence that treatment with selective serotonin reuptake inhibitors (SSRIs) during Covid-19 infection decreases the likelihood of a post-Covid condition, but there is no known research on treating post-Covid syndrome itself with SSRIs. This study used an exploratory questionnaire and found that 63,4% of 95 post-Covid syndrome patients reported a reasonably good to strong response to an SSRI. Outcomes were measured with three different measures that correlated strongly with each other. Brainfog and sensory overload decreased the most. Patients experienced improved well-being. The response to SSRIs in post-Covid conditions was explained by seven possible neurobiological mechanisms as reported in the recent literature. The promising results of this study should be followed by a randomized controlled trial.
... Several factors may be considered by treatment providers and consumers when supplying or purchasing medicine [26]. We found that the stated country of manufacture (source) of medicine was viewed as a proxy for quality, with suspicion of medicines made in India, China and Nigeria, which mirrors similar findings from other studies [10,14,27,28]. ...
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... Studies have shown that treatments involving acupuncture or medical devices tend to produce stronger effects than inert pills. 39,40,41 Similarly, placebo procedures that appear more costly tend to be more effective. 42,43 The various objects in the physical setting as well as the experimenter's behavior can demonstrate cues of credibility and competence, which additionally can promote placebo effects. ...
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Placebo effects raise some fundamental questions concerning the nature of clinical and medical research. This Element begins with an overview of the different roles placebos play, followed by a survey of significant studies and dominant views about placebo mechanisms. It then critically examines the concept of placebo and offers a new definition that avoids the pitfalls of other attempts. The main philosophical lesson is that background medical theories provide the ontology for clinical and medical research. Because these theories often contain incoherent and arbitrary classifications, the concept of placebo inherits the same messiness. The Element concludes by highlighting some impending challenges for placebo studies.
Osteoarthritis (OA) is the most common form of arthritis worldwide, affecting ~500 million people, yet there are no effective treatments to halt its progression. Without any structure-modifying agents, management of OA focuses on ameliorating pain and improving function. Treatment approaches typically have modest efficacy, and many patients have contraindications to recommended pharmacological treatments. Drug development for OA is hindered by the gradual and progressive nature of the disease and the targeting of established disease in clinical trials. Additionally, new medications for OA cannot receive regulatory approval without demonstrating improvements in both structure (pathological features of OA) and symptoms (reduced pain and/or improved function). In clinical trials, people with OA show high 'placebo responses', which hamper the ability to identify new effective treatments. Placebo responses refer to the individual variability in response to placebos given in the context of clinical trials and other settings. Placebo effects refer specifically to short-lasting improvements in symptoms that occur because of physiological changes. To mitigate the effects of the placebo phenomenon, we must first understand what it is, how it manifests, how to identify placebo responders in OA trials and how these insights can be used to improve clinical trials in OA. Leveraging placebo responses and effects in clinical practice might provide additional avenues to augment symptom management of OA.
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The authors integrate previous research that has investigated experimentally the influence of price, brand name, and/or store name on buyers' evaluations of prod¬uct quality. The meta-analysis suggests that, for consumer products, the relation¬ships between price and perceived quality and between brand name and perceived quality are positive and statistically significant. However, the positive effect of store name on perceived quality is small and not statistically significant. Further, the type of experimental design and the strength of the price manipulation are shown to significantly influence the observed effect of price on perceived quality.
Clinicians have long known that context is important in any medical treatment and that the words and attitudes of doctors and nurses can have great impact on the patient. There is now experimental evidence indicating that the medical context influences specific neural systems. The importance of the context is shown by the lesser effectiveness of hidden administrations of analgesics compared with open ones. Because the placebo effect is a context effect, its study has been useful in clarifying this complex issue. There are now several lines of evidence that placebo analgesia is mediated by endogenous opioids and placebo motor improvement by endogenous dopamine. Moreover, a placebo treatment is capable of affecting many brain regions in depressed patients. All these studies, taken together, lead to a neurobiological understanding of the events occurring in the brain during the interaction between the therapist and his or her patient.
Given the choice of waiting for an adverse outcome or getting it over with quickly, many people choose the latter. Theoretical models of decision-making have assumed that this occurs because there is a cost to waiting—i.e., dread. Using functional magnetic resonance imaging, we measured the neural responses to waiting for a cutaneous electric shock. Some individuals dreaded the outcome so much that, when given a choice, they preferred to receive more voltage rather than wait. Even when no decision was required, these extreme dreaders were distinguishable from those who dreaded mildly by the rate of increase of neural activity in the posterior elements of the cortical pain matrix. This suggests that dread derives, in part, from the attention devoted to the expected physical response and not simply from fear or anxiety. Although these differences were observed during a passive waiting procedure, they correlated with individual behavior in a subsequent choice paradigm, providing evidence for a neurobiological link between the experienced disutility of dread and subsequent decisions about unpleasant outcomes.
Placebo theory and its implications for research and clinical practice
  • E B Koshi
  • C A Short
Koshi EB, Short CA. Placebo theory and its implications for research and clinical practice. Pain Pract. 2007;7(1):4-20.
The contribution of desire and expectation to placebo analgesia: implications for new research strategies
  • D D Price
  • H L Fields
Price DD, Fields HL. The contribution of desire and expectation to placebo analgesia: implications for new research strategies. In: Harrington A, ed. The Placebo Effect: An Interdisciplinary Exploration. Cambridge, Massachusetts: Harvard University Press; 1999:118-119.