# Placebo Analgesia, Acupuncture and Sham Surgery

Authors: Tao Liu; Cui-ping Yu
Journal: Evidence-Based Complementary and Alternative Medicine
 (2011)

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## Abstract

Invasive procedures, such as surgery and acupuncture, are likely better than the others in terms of eliciting placebo analgesia. Understanding how invasive procedures can elicit enhanced placebo responses may provide new insights into mechanisms underlying placebo analgesia. In this essay, it is argued that sensory, cognitive and emotional factors are major determinants of the magnitude of placebo analgesia. Sham surgery and acupuncture are good examples of placebo interventions, which generate robust placebo responses through simultaneously manipulating such three factors.


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## Body

## 1.
Introduction

Although the intensity of pain correlates well with the degree of noxious stimulation, the perception of pain is not a linear phenomenon, reflecting the signal from peripheral nociceptors [1, 2], but rather heavily shaped by the
psychosocial context in which pain presents itself [3–5]. A striking example is placebo
analgesia which has increasingly been a research focus [6–10] for the potential
of leading to the development of novel approaches to the control
of chronic pain [11, 12]. Placebo analgesia does not happen
all the time and varies greatly across clinical and experimental
contexts. The essential question has been how and when placebo
analgesia is powerful and if placebo analgesia can have clinical
relevancy. Interestingly, sophisticated, invasive and painful
interventions such as surgery and acupuncture are thought to have
enhanced placebo effects [13–16]. Understanding how invasive
procedures can elicit enhanced placebo responses may provide new
insights into mechanisms underlying placebo analgesia.Acupuncture is an ancient Chinese therapy with its mode of
action unclear and efficacy inconclusive [17, 18]. Although
acupuncture has been defined as simplistically as the practice of
inserting one or more needles into specific sites on the body
surface for therapeutic purposes, converging evidence from theory
basis, clinical practice and clinical and basic science research
of acupuncture supports that acupuncture has more than needling
with its underlying cognitive and emotional context being an
integral part of this therapy [19].
But individual contributions of different components of
acupuncture to its therapeutic effects remain to be
identified.In the following, it is argued that cognitive,
sensory and emotional factors codetermine the magnitude of placebo
analgesia. Hence, enhanced placebo analgesia can be elicited
through manipulating such three factors. Sham surgery and
acupuncture are good examples of placebo interventions, which
generate robust placebo responses through simultaneously engaging
sensory, cognitive and emotional factors.


## 2. Factors That Determine the
Magnitude of Placebo Analgesia

There is no doubt that changes in pain cognition (e.g.
expectations and beliefs for pain) are fundamental factors
underlying placebo analgesia. Expectations for reduced pain
trigger placebo analgesia, and higher levels of less negative
expectations tend to produce larger placebo analgesic effects
[20]. However, expectations alone
have not always been found to produce placebo effects [21], and the magnitude of placebo
analgesia has been reported to be subject to the influences of
other factors. For example, an early study showed larger placebo
effects with more intense pain, indicating that sensory factors
contribute significantly to the magnitude of placebo analgesia
[22]. Moreover, it has been
reported that individuals are more likely to demonstrate a placebo
effect when they are feeling anxious than when they are not [23, 24],
supporting that emotional factors such as anxiety are other major
determinants of the magnitude of placebo analgesia [25]. Why have there been these different
approaches to mechanisms underlying placebo analgesia? One
possible explanation is that, although it is a critical factor
underlying placebo analgesia, expectation is not likely to operate
alone [26, 27], but sensory and emotional factors are also involved
in expectation-based placebo analgesia. In fact, the rationale to
assume that sensory, cognitive and emotional factors are involved
in placebo analgesia lies in the consideration that placebo
analgesia is the consequence of the same painful stimulus
presented in a changed cognitive and emotional context. Placebo
analgesia is triggered by cognitive factors but heavily shaped by
concurrent sensory and emotional factors—that is, sensory,
cognitive and emotional factors are major determinants of the
magnitude of placebo analgesia. These three factors vary greatly
across clinical and research contexts, which may account for the
considerable variability in the placebo effect itself.


## 3. Factors That
Contribute to Placebo-Induced Activation
of Endogenous Opioids

### 3.1. Role of Endogenous Opioids in Placebo
Analgesia

Although both opioid and non-opioid mechanisms
are responsible for placebo analgesia [28], an emerging idea is that expectation-based placebo
effects are opioid-mediated, but conditioned placebo effects may
depend on other mechanisms [7, 29–31]. Early pharmacological studies
show that placebo analgesia is antagonized by the opioid
antagonist naloxone [32, 33]. Additionally, the opioid-mediated
analgesic placebo response is enhanced with proglumide, a
cholecystokinin antagonist that modulates opioid activity [34]. Neuroimaging studies reveal that
placebo affects endogenous opioid activity in a number of
μ-opioid receptor regions that play central roles in pain and
affect [7, 35], and the same regions of the brain are affected by
both a placebo and the opioid agonist remifentanil, indicating a
shared brain mechanism involved in placebo- and opioid-induced
analgesia [9]. These findings
support a strong role for endogenous opioids in placebo analgesia,
and the extent to which endogenous opioids are activated may
determine the magnitude of placebo analgesia. However, little is
known about how opioid mechanisms come into play in
expectation-based placebo analgesia, and factors that determine
the functional state of placebo-activated endogenous opioids
remain to be identified.


### 3.2. Individual Contributions of Sensory,
Cognitive, and Emotional Factors to Placebo-Induced Activation of
Endogenous Opioids

Given that, as outlined above,
cognitive, sensory and emotional factors codetermine the magnitude
of placebo analgesia, it appears reasonable to propose that these
three factors are major determinants of the magnitude of
placebo-induced activation of endogenous opioids. When and only
when these three factors are simultaneously brought into full
play, can endogenous opioids be most effectively
activated.One of the more informative discoveries about
placebo-activated endogenous opioids is that highly
spatial-specific placebo responses, which are totally blocked by
the opioid antagonist naloxone, can only be obtained in the site
of the ongoing pain which is the target of spatially directed
expectation of pain reduction [20, 29, 36]. This suggests that placebo-activated
endogenous opioids have a precise and somatotopic organization
and, more importantly, the location of the ongoing pain determines
how endogenous opioids are somatotopically activated, hence in
which body parts placebo analgesic effects occur.Taken
together, sensory, cognitive and emotional factors contribute
differently to placebo analgesia through determining different
aspects of the functional state of placebo-activated endogenous
opioids: the intensity of painful stimulation, the level of
expectations for pain reduction and the degree of fear and anxiety
induced by pain codetermine of the magnitude of placebo-induced
activation of endogenous opioids; in addition, the location of the
ongoing pain determines how endogenous opioids are somatotopically
activated, hence the location of placebo analgesic
effects.


### 3.3. How Can Robust Placebo Analgesia Be
Induced in Specific Body Parts?

This identification of
individual contributions of sensory, cognitive and emotional
factors to placebo-induced activation of endogenous opioids
actually reveals how robust placebo analgesia can be induced in
specific body parts through manipulating these three factors. A
painful stimulus applied in an enhanced cognitive (positive
expectations for this painful stimulus) and emotional (fear and
anxiety induced by the application of this painful stimulus)
context could, as outlined above, to a greater extent activate
somatotopically organized endogenous opioids, thus producing
enhanced placebo analgesia in the location of the stimulus. More
importantly, if such a cognitively and emotionally engaged painful
stimulus is applied to the site of a clinical pain, then robust
placebo analgesia can be produced in the site of this clinical
pain—that is, the experienced intensity of this clinical pain
can be greatly reduced. Reasoning in this way, a given clinical
pain can be treated by applying another pain to specific body
parts in an enhanced cognitive and emotional context. For example,
knee pain can be treated by the application of another pain as a
therapy to the knee. But is there a clinically used placebo
therapy that depends on effectively engaging endogenous opioids
through simultaneously manipulating sensory, cognitive and
emotional factors? Acupuncture is a likely
candidate.


## 3.1. Role of Endogenous Opioids in Placebo
Analgesia

Although both opioid and non-opioid mechanisms
are responsible for placebo analgesia [28], an emerging idea is that expectation-based placebo
effects are opioid-mediated, but conditioned placebo effects may
depend on other mechanisms [7, 29–31]. Early pharmacological studies
show that placebo analgesia is antagonized by the opioid
antagonist naloxone [32, 33]. Additionally, the opioid-mediated
analgesic placebo response is enhanced with proglumide, a
cholecystokinin antagonist that modulates opioid activity [34]. Neuroimaging studies reveal that
placebo affects endogenous opioid activity in a number of
μ-opioid receptor regions that play central roles in pain and
affect [7, 35], and the same regions of the brain are affected by
both a placebo and the opioid agonist remifentanil, indicating a
shared brain mechanism involved in placebo- and opioid-induced
analgesia [9]. These findings
support a strong role for endogenous opioids in placebo analgesia,
and the extent to which endogenous opioids are activated may
determine the magnitude of placebo analgesia. However, little is
known about how opioid mechanisms come into play in
expectation-based placebo analgesia, and factors that determine
the functional state of placebo-activated endogenous opioids
remain to be identified.


## 3.2. Individual Contributions of Sensory,
Cognitive, and Emotional Factors to Placebo-Induced Activation of
Endogenous Opioids

Given that, as outlined above,
cognitive, sensory and emotional factors codetermine the magnitude
of placebo analgesia, it appears reasonable to propose that these
three factors are major determinants of the magnitude of
placebo-induced activation of endogenous opioids. When and only
when these three factors are simultaneously brought into full
play, can endogenous opioids be most effectively
activated.One of the more informative discoveries about
placebo-activated endogenous opioids is that highly
spatial-specific placebo responses, which are totally blocked by
the opioid antagonist naloxone, can only be obtained in the site
of the ongoing pain which is the target of spatially directed
expectation of pain reduction [20, 29, 36]. This suggests that placebo-activated
endogenous opioids have a precise and somatotopic organization
and, more importantly, the location of the ongoing pain determines
how endogenous opioids are somatotopically activated, hence in
which body parts placebo analgesic effects occur.Taken
together, sensory, cognitive and emotional factors contribute
differently to placebo analgesia through determining different
aspects of the functional state of placebo-activated endogenous
opioids: the intensity of painful stimulation, the level of
expectations for pain reduction and the degree of fear and anxiety
induced by pain codetermine of the magnitude of placebo-induced
activation of endogenous opioids; in addition, the location of the
ongoing pain determines how endogenous opioids are somatotopically
activated, hence the location of placebo analgesic
effects.


## 3.3. How Can Robust Placebo Analgesia Be
Induced in Specific Body Parts?

This identification of
individual contributions of sensory, cognitive and emotional
factors to placebo-induced activation of endogenous opioids
actually reveals how robust placebo analgesia can be induced in
specific body parts through manipulating these three factors. A
painful stimulus applied in an enhanced cognitive (positive
expectations for this painful stimulus) and emotional (fear and
anxiety induced by the application of this painful stimulus)
context could, as outlined above, to a greater extent activate
somatotopically organized endogenous opioids, thus producing
enhanced placebo analgesia in the location of the stimulus. More
importantly, if such a cognitively and emotionally engaged painful
stimulus is applied to the site of a clinical pain, then robust
placebo analgesia can be produced in the site of this clinical
pain—that is, the experienced intensity of this clinical pain
can be greatly reduced. Reasoning in this way, a given clinical
pain can be treated by applying another pain to specific body
parts in an enhanced cognitive and emotional context. For example,
knee pain can be treated by the application of another pain as a
therapy to the knee. But is there a clinically used placebo
therapy that depends on effectively engaging endogenous opioids
through simultaneously manipulating sensory, cognitive and
emotional factors? Acupuncture is a likely
candidate.


## 4. Is There a Clinically Used Placebo
Therapy?

Acupuncture is an ancient Chinese therapy,
most commonly used for pain control, involving inserting needles
into specific parts of the body. However, its mechanisms of action
are not well understood, and controversy regarding its clinical
efficacy remains [37]. Initially,
research attention has therefore been solely focused on the needle
insertion due to the beliefs that if acupuncture is efficacious it
must be specifically due to this technical procedure. The
essential question concerning the efficacy of acupuncture is
therefore that if acupuncture generates specific effects superior
to its placebo control. Randomized placebo-controlled trials are
therefore introduced to assess the specific efficacy of needle
insertion on the basis of the biomedical consideration that
efficacious therapy is therapy that proves to be superior to its
placebo control in a randomized controlled trial. When the
majority of randomized controlled trials of acupuncture fails to
show effects beyond a placebo response [38, 39], acupuncture has
been dismissed as nothing more than placebo [40]. However, to say that acupuncture is not better than
placebo does not mean that it does nothing. In fact, the essential
issue concerning the effectiveness of acupuncture is not if
acupuncture has more than placebo effects, but rather how
acupuncture can produce such robust placebo effects as to have
clinical relevancy.


### 4.1. Is Acupuncture an Enhanced
Placebo?

Research data support the critical role of
beliefs and expectations in the effectiveness of acupuncture. A
recent study concluded that the effectiveness of acupuncture was
significantly associated with higher outcome expectations [41], and therefore how patients are
informed about the trial of acupuncture they take part in may
greatly influence trial outcomes [42]. Another study went even a step further reporting
that patient’s beliefs and expectations (determined by the
perceived assignment to real acupuncture or a placebo) had a
greater impact on treatment outcomes than did the actual treatment
itself [43]. Furthermore, research
findings from neuroimaging studies on acupuncture analgesia show
that acupuncture may act on similar neural networks as placebo
(expectations for reduced pain) in producing pain relief [44–47]. Indeed, it has been suggested that it is not
meaningful to split acupuncture into specific and non-specific
elements and the use of placebo and sham controlled trial designs
in evaluating acupuncture may generate false-negative results
[48]. In line with this suggestion,
considering the critical role played by expectations and beliefs
in the effectiveness of acupuncture, it has been proposed that
acupuncture is actually an enhanced placebo and necessarily
comprises three integral and indispensable components, which are
of the same importance in ensuring the effectiveness of
acupuncture, including needle insertion (spatial-specific painful
stimulation), culture-enhanced positive beliefs and benefit
expectations for needle stimulation (cognitive context), and fear
and anxiety induced by the perceived invasiveness of needle
insertion (emotional context) [19].
This new view of acupuncture as an enhanced placebo warrants a new
look at specific and non-specific elements involved in the
clinical administration of acupuncture and challenges the present
consideration of randomized controlled trials as gold standard in
evaluating the efficacy of acupuncture, for it is unlikely
meaningful to evaluate the effectiveness of a placebo therapy such
as acupuncture with placebo-controlled trial designs.


### 4.2. Cognitive and
Emotional Context Underlying Acupuncture

Culture can
have profound impacts on medicine through shaping individuals’
beliefs [49]. Acupuncture is
definitely a culture-based therapy embedded in unique beliefs and
rituals [37, 50, 51], allowing patients
to have elevated positive beliefs and benefit expectations on this
therapy. Furthermore, comprehensive and intimate
acupuncturist–patient relationship is another factor
contributing to enhanced benefit expectations for this therapy
[52]. Furthermore, fear and anxiety
comprise the characteristic emotional context in which acupuncture
is administered. Acupuncture is, at any rate, an invasive
procedure which can never fail to cause considerable levels of
fear and anxiety in the patient while receiving this treatment,
even for those who repeatedly receive this treatment. Actually,
this invasiveness induced fear and anxiety can make great impacts
on the patient’s mind: a wide range of adverse effects occurring
before/during needle administration can be attributable to the
patient’s fear and anxiety, including, just list a few, severe
nausea, actual fainting, severe dizziness, heavy sweating and
vomiting [53].


### 4.3. Why Does Acupuncture
Induce Enhanced Placebo Analgesia?

These observations
strongly point to the assumption that acupuncture depends on the
administration of invasive procedures (i.e., needle insertion that
produces spatial-specific painful stimulation) in an enhanced
cognitive and emotional context to make therapeutic effects. Such
three integral components of acupuncture, as outlined above, can
most effectively activate somatotopically organized endogenous
opioids and, thus, generate robust placebo effects in specific
parts of the body (the location of the target pain). This is
consistent with studies showing that acupuncture analgesia is
largely mediated by endogenous opioids [54–56]. Most importantly, according to
traditional Chinese medicine (TCM) meridian theory,
spatial-specific needle stimulation induces therapeutic effects
only in specific parts of the body, not only in the site of needle
stimulation (local effects) but also at some distance from the
site of stimulation along a specific meridian (distal effects).
That is, pain of different locations and tissues origins needs to
be treated by inserting needles into different parts of the body.
Acupuncture is therefore a good example of clinically used placebo
therapies which produce clinically relevant placebo responses
through simultaneously manipulating sensory, cognitive and
emotional factors. That explains why acupuncture is provided in
such a sophisticated manner and how clinical provision of
acupuncture can elicit robust placebo effects.The level of
placebo expectations, which is a major determinant factor of the
magnitude of placebo analgesia, varies greatly across clinical and
experimental contexts. At one end of the scale are less negative
expectations for the target pain (i.e., expectations for the
reduction of the target pain) as with non-invasive placebos such
as placebo cream, pills, words and practitioner-patient
relationships, whereas at the other end of the scale are positive
expectations (i.e., positive beliefs and benefit expectations) for
a painful stimulus administered as a therapy as with invasive
placebos such as acupuncture. There is no doubt that positive
expectations are definitely different in nature from, and
obviously of a higher level than, less negative expectations.
Compared with that less negative expectations for the target pain
do not elicit clinically relevant placebo analgesia, positive
expectations for a spatial-specific painful stimulation induced by
invasive procedures could more effectively activate
somatotopically organized endogenous opioids, thus generating
enhanced placebo analgesia of clinically relevancy in the location
of the target pain (Figure1). In
short, enhanced placebo responses of acupuncture do not result
directly from less negative expectations for the target pain but
rather indirectly from positive expectations for needle
stimulation administered as a therapy. Although pain is
undoubtedly an aversive and negative experience and can hardly be
associated with positive expectations, clinical administration of
acupuncture successfully induces positive beliefs and benefit
expectations for a therapeutic pain through which endogenous
opioids can be most effectively activated. Acupuncture can
therefore be viewed as depending on “positive” pain to cure
negative pain.Figure 1
Compared with non-invasive placebos (such as placebo creams, pills and words), which induce less negative (neutral at best) expectations for the target pain, invasive placebos such as sham surgery and acupuncture induce positive (neutral at least) expectations for a painful stimulus administered as a therapy, thus producing clinically relevant placebo analgesia.


## 4.1. Is Acupuncture an Enhanced
Placebo?

Research data support the critical role of
beliefs and expectations in the effectiveness of acupuncture. A
recent study concluded that the effectiveness of acupuncture was
significantly associated with higher outcome expectations [41], and therefore how patients are
informed about the trial of acupuncture they take part in may
greatly influence trial outcomes [42]. Another study went even a step further reporting
that patient’s beliefs and expectations (determined by the
perceived assignment to real acupuncture or a placebo) had a
greater impact on treatment outcomes than did the actual treatment
itself [43]. Furthermore, research
findings from neuroimaging studies on acupuncture analgesia show
that acupuncture may act on similar neural networks as placebo
(expectations for reduced pain) in producing pain relief [44–47]. Indeed, it has been suggested that it is not
meaningful to split acupuncture into specific and non-specific
elements and the use of placebo and sham controlled trial designs
in evaluating acupuncture may generate false-negative results
[48]. In line with this suggestion,
considering the critical role played by expectations and beliefs
in the effectiveness of acupuncture, it has been proposed that
acupuncture is actually an enhanced placebo and necessarily
comprises three integral and indispensable components, which are
of the same importance in ensuring the effectiveness of
acupuncture, including needle insertion (spatial-specific painful
stimulation), culture-enhanced positive beliefs and benefit
expectations for needle stimulation (cognitive context), and fear
and anxiety induced by the perceived invasiveness of needle
insertion (emotional context) [19].
This new view of acupuncture as an enhanced placebo warrants a new
look at specific and non-specific elements involved in the
clinical administration of acupuncture and challenges the present
consideration of randomized controlled trials as gold standard in
evaluating the efficacy of acupuncture, for it is unlikely
meaningful to evaluate the effectiveness of a placebo therapy such
as acupuncture with placebo-controlled trial designs.


## 4.2. Cognitive and
Emotional Context Underlying Acupuncture

Culture can
have profound impacts on medicine through shaping individuals’
beliefs [49]. Acupuncture is
definitely a culture-based therapy embedded in unique beliefs and
rituals [37, 50, 51], allowing patients
to have elevated positive beliefs and benefit expectations on this
therapy. Furthermore, comprehensive and intimate
acupuncturist–patient relationship is another factor
contributing to enhanced benefit expectations for this therapy
[52]. Furthermore, fear and anxiety
comprise the characteristic emotional context in which acupuncture
is administered. Acupuncture is, at any rate, an invasive
procedure which can never fail to cause considerable levels of
fear and anxiety in the patient while receiving this treatment,
even for those who repeatedly receive this treatment. Actually,
this invasiveness induced fear and anxiety can make great impacts
on the patient’s mind: a wide range of adverse effects occurring
before/during needle administration can be attributable to the
patient’s fear and anxiety, including, just list a few, severe
nausea, actual fainting, severe dizziness, heavy sweating and
vomiting [53].


## 4.3. Why Does Acupuncture
Induce Enhanced Placebo Analgesia?

These observations
strongly point to the assumption that acupuncture depends on the
administration of invasive procedures (i.e., needle insertion that
produces spatial-specific painful stimulation) in an enhanced
cognitive and emotional context to make therapeutic effects. Such
three integral components of acupuncture, as outlined above, can
most effectively activate somatotopically organized endogenous
opioids and, thus, generate robust placebo effects in specific
parts of the body (the location of the target pain). This is
consistent with studies showing that acupuncture analgesia is
largely mediated by endogenous opioids [54–56]. Most importantly, according to
traditional Chinese medicine (TCM) meridian theory,
spatial-specific needle stimulation induces therapeutic effects
only in specific parts of the body, not only in the site of needle
stimulation (local effects) but also at some distance from the
site of stimulation along a specific meridian (distal effects).
That is, pain of different locations and tissues origins needs to
be treated by inserting needles into different parts of the body.
Acupuncture is therefore a good example of clinically used placebo
therapies which produce clinically relevant placebo responses
through simultaneously manipulating sensory, cognitive and
emotional factors. That explains why acupuncture is provided in
such a sophisticated manner and how clinical provision of
acupuncture can elicit robust placebo effects.The level of
placebo expectations, which is a major determinant factor of the
magnitude of placebo analgesia, varies greatly across clinical and
experimental contexts. At one end of the scale are less negative
expectations for the target pain (i.e., expectations for the
reduction of the target pain) as with non-invasive placebos such
as placebo cream, pills, words and practitioner-patient
relationships, whereas at the other end of the scale are positive
expectations (i.e., positive beliefs and benefit expectations) for
a painful stimulus administered as a therapy as with invasive
placebos such as acupuncture. There is no doubt that positive
expectations are definitely different in nature from, and
obviously of a higher level than, less negative expectations.
Compared with that less negative expectations for the target pain
do not elicit clinically relevant placebo analgesia, positive
expectations for a spatial-specific painful stimulation induced by
invasive procedures could more effectively activate
somatotopically organized endogenous opioids, thus generating
enhanced placebo analgesia of clinically relevancy in the location
of the target pain (Figure1). In
short, enhanced placebo responses of acupuncture do not result
directly from less negative expectations for the target pain but
rather indirectly from positive expectations for needle
stimulation administered as a therapy. Although pain is
undoubtedly an aversive and negative experience and can hardly be
associated with positive expectations, clinical administration of
acupuncture successfully induces positive beliefs and benefit
expectations for a therapeutic pain through which endogenous
opioids can be most effectively activated. Acupuncture can
therefore be viewed as depending on “positive” pain to cure
negative pain.Figure 1
Compared with non-invasive placebos (such as placebo creams, pills and words), which induce less negative (neutral at best) expectations for the target pain, invasive placebos such as sham surgery and acupuncture induce positive (neutral at least) expectations for a painful stimulus administered as a therapy, thus producing clinically relevant placebo analgesia.


## 5. Why Does Sham Surgery Generate Robust Placebo Analgesia?

This new account of enhanced placebo analgesia of acupuncture is supported by further evidence from randomized sham-controlled trials of invasive interventions for pain. Clinical trials of surgery have seldom included placebo surgery as a control, owing to ethical concerns [57, 58]. However, occasionally used sham-controlled surgical trials dramatically showed that sham surgical procedures could be as effective as real procedures in terms of the improvements in subjective measures such as pain and function [59–62]. These studies demonstrate how much of the success of operative procedures for pain reported by observational trials is due to the placebo effect [63].But why can sham surgery elicit especially robust placebo analgesia of clinical relevancy? A possible explanation is that sham surgery depends on the administration of invasive procedures such as skin incisions and sutures (which produce spatial-specific painful stimulation) in an enhanced cognitive and emotional context to generate robust placebo analgesia.


### 5.1. Cognitive and Emotional Context Underlying Sham Surgery

Surgery is particularly meaningful in a culture rich in machines and tools and therefore induces a profound meaning response in modern medical practice [49, 64, 65]. What features clinical administration of surgery is enhanced positive beliefs and benefit expectations for invasive procedures: surgeons are among the elite of medical practitioners; surgical procedures usually have compelling rational explanations, which drug treatments often do not; in addition, the invasive nature itself of surgery is also an important contributing factor to enhanced positive beliefs and benefit expectations. Furthermore, there is no doubt that fear and anxiety comprise the characteristic emotional context in which surgery is administered, for surgery is obviously invasive and can cause inevitable pain and most likely blood shedding.


### 5.2. Why Does Sham Surgery Elicit Enhanced Placebo Analgesia?

On the basis of these considerations, it is reasonable to propose that sensory (spatial-specific painful stimulation induced by sham procedures), cognitive (positive beliefs and benefit expectations for the painful stimulation) and emotional (fear and anxiety induced by the perceived invasiveness of surgical procedures) factors are simultaneously engaged by the administration of sham surgery. A combination of these three factors, as outlined above, could most effectively activate somatotopically organized endogenous opioids to produce clinically relevant analgesic effects in specific body parts (the location of the target pain). In this regard, interestingly, sham surgery and acupuncture can be considered to be analogous in terms of a spatial-specific painful stimulus administered in an enhanced cognitive and emotional context. This proposition is convincingly supported by research findings from recent sham-controlled trials of invasive interventions for pain of various locations. A large-scale, randomized controlled trial of arthroscopic surgery for knee osteoarthritis reported that sham operations (which produce spatial-specific painful stimulation) administered in the skin of the knee, which elicit robust analgesic effects in the knee, are no less effective for knee pain than real procedures [60]. Not coincidently, a recent high-quality randomized controlled trial of vertebroplasty for painful osteoporotic vertebral fractures drew similar conclusions that sham operations administrated in the affected vertebral body can as effectively reduce pain in that area as real procedures [62].


## 5.1. Cognitive and Emotional Context Underlying Sham Surgery

Surgery is particularly meaningful in a culture rich in machines and tools and therefore induces a profound meaning response in modern medical practice [49, 64, 65]. What features clinical administration of surgery is enhanced positive beliefs and benefit expectations for invasive procedures: surgeons are among the elite of medical practitioners; surgical procedures usually have compelling rational explanations, which drug treatments often do not; in addition, the invasive nature itself of surgery is also an important contributing factor to enhanced positive beliefs and benefit expectations. Furthermore, there is no doubt that fear and anxiety comprise the characteristic emotional context in which surgery is administered, for surgery is obviously invasive and can cause inevitable pain and most likely blood shedding.


## 5.2. Why Does Sham Surgery Elicit Enhanced Placebo Analgesia?

On the basis of these considerations, it is reasonable to propose that sensory (spatial-specific painful stimulation induced by sham procedures), cognitive (positive beliefs and benefit expectations for the painful stimulation) and emotional (fear and anxiety induced by the perceived invasiveness of surgical procedures) factors are simultaneously engaged by the administration of sham surgery. A combination of these three factors, as outlined above, could most effectively activate somatotopically organized endogenous opioids to produce clinically relevant analgesic effects in specific body parts (the location of the target pain). In this regard, interestingly, sham surgery and acupuncture can be considered to be analogous in terms of a spatial-specific painful stimulus administered in an enhanced cognitive and emotional context. This proposition is convincingly supported by research findings from recent sham-controlled trials of invasive interventions for pain of various locations. A large-scale, randomized controlled trial of arthroscopic surgery for knee osteoarthritis reported that sham operations (which produce spatial-specific painful stimulation) administered in the skin of the knee, which elicit robust analgesic effects in the knee, are no less effective for knee pain than real procedures [60]. Not coincidently, a recent high-quality randomized controlled trial of vertebroplasty for painful osteoporotic vertebral fractures drew similar conclusions that sham operations administrated in the affected vertebral body can as effectively reduce pain in that area as real procedures [62].


## 6. Conclusion

Previous studies focused on the role of cognitive factors (expectations and beliefs) in placebo responding. However, the present hypothesis argues that sensory, cognitive and emotional factors are simultaneously at work during placebo analgesia. Furthermore, clinically relevant placebo analgesia can be produced in specific body parts through the manipulation of such three factors as in the case of acupuncture and sham surgery. That explains why invasive procedures, such as acupuncture and sham surgery, are better than the others in terms of eliciting placebo analgesia. Acupuncture is a clinically used placebo therapy, theory basis and clinical administration of which highlight one of the best, if not the best, manners through which enhanced placebo effects can be produced in specific body parts (the site of the target pain). Research into the mode of action of acupuncture will shed direct light on neural mechanisms underlying placebo analgesia and vice versa.



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*Source: 943147-2011-03-13.xml*