Opioid and Placebo

Analgesia Share the Same Network

Predrag Petrovic, MD, PhD

The relationship between the endogenous opioid system and placebo analgesia has fas-
cinated the research community for decades. Using functional imaging methods, it is now
possible to study the underlying opioid and placebo processes in the brain. Such studies
have shown overlapping activity in the anterior cingulate cortex (ACC) and the insula
stretching into the orbitofrontal cortex. Because the ACC is involved in top-down atten-
tional regulation, this region may mediate the interaction between higher cognitive pro-
cesses and the endogenous opioid network. Moreover, data also indicate that the ACC may
exert its modulation through the brainstem opioid network. The orbitofrontal cortex also
shows placebo-dependent activation, but it does not have similar access to the opioid
network. Thus, this region may be involved in other aspects of the placebo response such
as processing treatment expectations.
Semin Pain Med 3:31-36 2005 Elsevier Inc. All rights reserved.

KEYWORDS placebo-analgesia, pain, opioid, positron emission tomography, functional mag-

netic resonance imaging, anterior cingulate cortex, insula, orbitofrontal cortex, brainstem

P lacebo analgesia research had the first major scientific

breakthrough when it was discovered that the placebo
effect depended on the endogenous opioid system,1 a finding
the endogenous opioid system in the cortex and the brain-
stem.

that has been replicated in several studies (eg, refs. 2-4).

Since this discovery, complex and well-designed behavioral
designs have shown strong relationships between placebo
analgesia and treatment expectation,2,5-8 drug conditioning,2
autonomic correlates,4 and somatotopic dependence.3 Re-
cently, a third important step has been taken in placebo re-
search, that is, unraveling the underlying neuronal correlates
involved in the placebo analgesia response using positron
emission tomography (PET) or functional MRI (fMRI).9-12
Placebo analgesia is a unique phenomenon because it is
one of few higher cognitive top-down processes in which a
known specific neuromodulatory system operates, ie, the
opioid system. However, the endogenous opioid system is
also involved in a broad range of emotional processes shown
both in animals and in humans.13-15 This knowledge makes
the placebo effect interesting not only for understanding pain
regulation but emotional regulation in general. This review
article will try to relate the described placebo network9-12 to
Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Swe-
den.
Address correspondence to Predrag Petrovic, MD, MPH, MRC, Dept Clinical
Neuroscience, Karolinska Institute/Karolinska Hospital, 171 76 Stock-
holm, Sweden. E-mail: predrag.petrovic@cns.ki.se
The Opioid System in the Brain
Opioid receptors in the central nervous system (CNS) are
found in the entire neuroaxis, eg, in the cortex, brainstem,
and spinal cord.16-21 Although these receptors are widespread
throughout the CNS, the localization is not diffuse but highly
regional. It has been proposed that networks containing opi-
oid receptors may exert analgesic effects through several dif-
ferent mechanisms.22 These include modulation of spinal
noxious input (in the dorsal horn and in the ascending path-
ways), direct control of cortical and brainstem structures that
are involved in pain processing, or regulation of the ascend-
ing forebrain systems. At present, the modulation of the spi-
nal cord has been best described.17,18
The brainstem opioid system consists of a network of re-
gions, including the periaqueductal gray (PAG), the parabra-
chial nucleus, and the rostral ventromedial medulla , which
are critically involved in descending opioid dependent anal-
gesia (for a complete review, see refs. 17,18).
The opioid receptor network is less characterized in the
cortex, especially in the more developed human brain. How-
ever, autoradiographic studies of postmortem human and
primate brains and PET studies of opioid receptors in the
human subjects have started to reveal a cortical opioid sys-

1537-5897/05/$-see front matter 2005 Elsevier Inc. All rights reserved. 31

doi:10.1016/j.spmd.2005.02.005
32 P. Petrovic

Figure 1 Comparison between

placebo-induced activity and
opioid-induced activity in the
cortex. The short-lasting mu-
selective opioid remifentanil
activated cortical areas such as
the ACC (a) and the anterior
insula/temporopolar cortex
(stretching into the Obfc) (b).
However, the activity in the
Obfc was only observed in the
conjunction between the insu-
la/temporopolar cortex and the
Obfc, possibly representing
only smoothing effect of the
data, ie, the core region of the
Obfc was not activated by
remifentanil (c). Placebo-de-
pendent activity was observed
in the rACC (d), the right ante-
rior insula (e), and in an exten-
sive part of the lateral Obfc
dominated in the right hemi-
sphere (f). (The image is pre-
sented on an SPM-template at
www.fil.ion.ucl.ac.uk/spm.)
(Color version of figure is
available online.)

tem. The autoradiographic studies indicate high concentra-
tions of opioid receptors not only in the brainstem, eg, the
PAG, the intralaminar, and medial thalamic nuclei, but also
in the cingulate cortex and prefrontal cortex.19-21 These and
other animal studies have suggested that the anterior cingu-
late cortex (ACC) has one of the highest levels of opioid
receptor bindings in the cortex.23
PET studies using radioactive opioid [11C]-diprenor-
phine, which indicates the mu-, delta-, and kappa-opioid
receptor availability, have confirmed previous animal and
human autoradiography findings.24-26 Although no quantita-
tive analysis of the entire brain has been presented, the opioid
receptor images from these PET studies suggest a high opioid
receptor concentration in the insula and the frontal cortex.
Raw data indicate that the binding potential is highest in the
rostral parts of the anterior cingulate cortex (rACC).24-26 The
receptor imaging studies have also indicated high opioid re-
ceptor binding potential in basal ganglia and thalamus.
A similar network has showed increased neuronal activity
(using PET and measuring the regional blood flow as an
index of the underlying neuronal activity) during treatment
with opioid-receptor agonists, such as remifentanil and fen-
tanyl.9,27-30 In 2 of the studies, it was shown that remifentanil,
a mu-opioid compound with a short half life, increases the
activity in several regions known to be involved in pain-
processing and containing a high concentrations of opioid
receptors (eg, Fig. 1).9,30 Opioid-dependent increases were
observed in the caudal and rostral ACC, midanterior insula,
stretching into the orbitofrontal/temporopolar cortex, and in
the brainstem. Common for all previously presented func-
tional imaging studies was an observed activity increase in
the rostral ACC in response to opioid treatment. Thus, it may
be suggested that a relationship exists between the opioid
system and the rACC. In summary, autoradiographic studies,
opioid-receptor imaging studies, and functional imaging
studies all indicate that a specific opioid-rich network exists
in the cortex that includes the ACC and the anterior insula.
Conditions That Activate
the Endogenous Opioid System
The complexity of the endogenous opioid network indicates
that it is an important regulatory system for the organism.
However, it is less elaborated in which natural situations
these systems are active and their role for increasing the
chances of the survival of the organism.
In animal studies, contexts that induce fear and stress have
been described as important for the activation of the endog-
enous opioid system, ie, fear- or stress-related analgesia.31
This state has been induced either using noxious shocks,
conditioning a noxious shock with an neutral stimulation (ie,
conditioned stress induced analgesia) or setting up a context
in which fear is thought to be induced in the animal, eg,
putting an animal in the same cage as its predator (see ref. 31
for details). These triggers will activate an opioid system me-
diated via the amygdala, which then activates the brainstem
opioid system via the PAG.31
It has been hypothesized that several contexts may be im-
portant for activating endogenous opioid systems for the in-
Opioid and placebo analgesia share the same network
duction of analgesia in humans, although a great deal of
variability exists in these studies.17,32 The placebo response is
probably the best-described experimental situation in which
the endogenous opioid system in humans is naturally acti-
vated1-4 and, thus, research on the placebo response is of
general importance also for understanding the endogenous
opioid system.
Apart from the analgesic function the opioid subsystems
may be specifically involved in different motivational and
mood regulations. Emotional responses in rats have been
suggested to be dependent on the opioid system.13,31 Even
more intriguing, it has been suggested that the mu-opioid
system may be involved in emotional processing and regula-
tion in humans.14,15 Thus, its role is not just to regulate pain
perception but to modulate the general state of the organism,
which also includes a change of the perceived pain. This role
implies that the opioid effect can be understood only in rela-
tion to the external context and the internal state (eg, moti-
vation and emotion).
Placebo and Cognition
Although opioid conditioning is one possible mechanism in-
ducing analgesia,2 the placebo effect also must be accessible
via higher cognitive processes because it is clearly affected by
beliefs, attitudes, and conscious expectations.32,33 Nonspe-
cific stimuli in the context, which are coded in higher cogni-
tive networks, may both induce and modulate placebo anal-
gesia. An impressing and well-studied higher cognitive
process that influences placebo response is expectations of a
treatment outcome.2,5-8 Thus, the belief that a treatment is
effective directly correlates with the degree of placebo anal-
gesia.6 Therefore the placebo effect must also contain a cog-
nitive process converting the expectation to a changed pain
processing induced by top-down modulation.
Apart from containing a large concentration of opioid re-
ceptors, the ACC is involved in higher cognitive attentional
tasks. Modern theories of attention suggest that the ACC is
involved in conflict monitoring or conflict resolution.34-36 A
conflict implies that two different processes compete for the
attentional space in the brain and therefore must be con-
trolled.37 The meta-analysis by Bush and coworkers35
showed that the ACC may be divided into a cognitive (mid-
caudal ACC) and an emotional region (rACC). Moreover, the
authors suggested that the rACC also is involved attentional
tasks but in the emotionalmotivational domain. Because
pain may be viewed as a homeostatic emotion38 and a there-
fore a conflicting emotional process competing for the atten-
tional space, it may be suggested that the rACC is involved in
attentional processing on the pain experience.39
Placebo Analgesia
and the Opioid Network
We have suggested9 that the rACC is involved in the interac-
tion between attention and the opioid system in placebo an-
algesia because of the dense concentration of opioid recep-
33
Figure 2 Placebo-dependent increases and decreases in the ACC.
Increased activity is indicated with gray, and decreased activity is
indicated with white circles. In the studies by Wager and cowork-
ers,10 the activity increases were observed in the anticipation phase
(gray circles), whereas the decreases were observed in the stimula-
tion phase (white circles). In the study by Lieberman and cowork-
ers,11 only decreases were observed in the ACC (white circle). (The
image is presented on an SPM-template at www.fil.ion.ucl.ac.uk/
spm.)
tors found in the ACC23 and its involvement in tasks
requiring conflict resolution (as mentioned previously).35,36
Thus, rACC may be viewed as the region in which higher
cognitive attentional processes have access to a specific neu-
romodulatory system. In line with this suggestion, we per-
formed a PET study in which an increased neuronal activity
was observed during placebo analgesia in the same region of
rostral ACC as maximally activated when the same subjects
were treated with opioids9 (Fig. 1). Another activation ob-
served in the placebo condition encompassed the orbitofron-
tal cortex (Obfc) stretching in to the anterior insula.
Placebo-dependent activation of the rACC9 has been rep-
licated recently (Fig. 2).10-12 A similar ACC activation was
described by Bingel and coworkers12 in placebo-induced an-
algesia. In the article by Wager and coworkers,10 2 placebo
studies were performed while the underlying neuronal activ-
ity was studied using functional MRI in both the anticipation
and the induction phase of a painful stimulus. Both studies
showed placebo-dependent activations of the rACC as well as
in the lateral Obfc in the anticipation phase. However, these
activations were not observed during the pain stimulation
itself. Instead, decreased activations in the ACC were ob-
served in the placebo pain phase. The authors suggest that
when there is a preparatory phase, the placebo-dependent
modulatory effect may be induced before the actual painful
stimulation, leading to a decreased pain processing during
the stimulation. This is a fascinating suggestion, indicating
that we are able to activate the endogenous system in a pre-
perceptive manner. The decreased activation observed some-
34
Figure 3 Placebo-dependent increases in the lateral Obfc. Increased
activity is indicated with gray circles. In both studies by Wager and
coworkers,10 the placebo activations of the Obfc were observed in
the anticipation phase. In all other studies, the Obfc activations were
observed in the stimulation phase. The effect was not significant in
study 2 by Wager and coworkers possibly because there were prob-
lems with attenuation effects in this region. (The image is presented
on an SPM-template at www.fil.ion.ucl.ac.uk/spm.)
what later would then indicate an attenuated processing of
pain unpleasantness processed in the ACC.40
In the study by Lieberman and coworkers11 no increased
placebo-dependent activation was observed in the rACC; in-
stead, a negative correlation was observed between the pla-
cebo degree and the activity in mid-caudal ACC (a more
posterior region of the ACC). However, in this study the
placebo effect was induced during a 2-week period and acute
modulatory effects were not studied. The 2 last described
articles10,11 point to some of the difficulties in the study of
higher cognitive modulations of pain, that is, similar regions
in the ACC are involved in processing perception of pain
unpleasantness (possibly inducing relative decrease of ACC
activity during placebo treatment) as well as in pain regula-
tion (possibly inducing relative increases of ACC activity dur-
ing placebo treatment). Although the pain regulatory activa-
tions seem to be somewhat more rostral39 the 2 areas of
activity may partly overlap and the pain-related decreases
may attenuate placebo induced increase in activity. Never-
theless, 4 of the 5 presented placebo experiments9,10,12 indi-
cate the involvement of the rACC in placebo effect (Fig. 2).
When it comes to the orbitofrontal cortex, 4 of the pre-
sented functional imaging experiments indicate a placebo-
dependent activation of this region9-11 (Fig. 3) with a prefer-
ence for the right Obfc.9,11 Few functional imaging studies on
the opioid effect have described extensive or any opioid-
related activations of the Obfc, which may indicate that other
processing components of the placebo response are com-
puted in this region. As an example, we observed placebo-
P. Petrovic
dependent increases in the Obfc that were clearly more ex-
tensive than the opioid-dependent increases (Fig. 1).9 The
opioid-induced Obfc activation was present only on the bor-
der between the temporopolar/insular activations. In fact, the
activations observed in the Obfc may more represent a
smoothing effect of the data. A key function of the Obfc is to
monitor and modulate the motivational value of external
stimuli based on their coupling to primary re-enforcers41-44 to
perform a goal-directed behavior.45 Because the Obfc is in-
volved in attributing external stimuli a relative value depend-
ing on the internal states and external contexts it is tempting
to suggest that this region is involved in inducing the expec-
tation of treatment and how the expectation should affect the
pain experience, which may be a process preceding the opi-
oid-dependent modulation of pain perception. Such a bias
signal may be used by the ACC that is in a position to interact
with the endogenous opioid system (Fig. 4).
The placebo-induced activity in the Obfc also stretched
into the temporopolar region/anterior insula, which is inter-
esting because the insula has a high concentration of opioid
receptors indicated by both receptor imaging and functional
imaging studies (as mentioned previously) and also has been
suggested to be involved in a meta-representation of the state
of the body associated with emotional awareness.38
Interaction Between rACC
and Brainstem Opioid Systems
It has previously been proposed that the opioid system in the
ACC has access to the powerful opioid system in the brain-
stem (Fig. 4).18,23 We suggested that this is one of the mech-
anisms by which the higher cognitive systems in the ACC
may influence nociceptive input to the brain and thereby
pain perception.9 We performed a regression analysis and
observed that both in placebo analgesia and opioid analgesia
the rACC activity correlated with the brainstem, a finding
that was not observed for the pain condition without treat-
ment. Although no causality can be shown, the data indicate
that such a mechanism may exist. A similar regression has
been replicated in the placebo analgesia study by Bingel and
coworkers.12 Moreover, a similar functional connection has
been shown in pain-distraction46 and prolonged tonic pain,47
suggesting that other pain regulatory conditions may involve
ACC-mediated opioid-dependent control of the brainstem
opioid system. Wager and coworkers did not supply such an
analysis with the rACC but showed that also the orbitofrontal
cortex has a similar functional connectivity with the brain-
stem.10 This supports the conclusion that both regions work
in the same modulatory network.
Placebo Responders
and the Opioid System
Several studies have indicated that there is a large variability
between individual subjects in the placebo response. The
reason for this is probably multifactorial. One factor that may
crucially affect the placebo analgesic response is the under-
Opioid and placebo analgesia share the same network 35

Figure 4 The opioid network in the cortex and the brainstem and its interaction with the orbitofrontal cortex. There is
an opioid-rich network in the brainstem, including the periaqueductal gray (PAG), the parabracial nucleus (PBN), and
the rostral ventrolateral medulla (RVM). This network may be controlled by the opioid-dependent processes in the
amygdala in fear-induced analgesia. We suggest that the ACC, as a part of an opioid-rich network also including the
anterior insula and the Obfc, is similarly involved in brainstem regulation in placebo analgesia. Given that the Obfc is
not highly activated by opioids, it may be involved processing other components in the placebo response, such as
treatment expectations. (The image is presented on an SPM-template at www.fil.ion.ucl.ac.uk/spm.)

lying opioid system, that is, it would not possible to induce
opioid-dependent placebo analgesia in a subject who is lack-
ing an endogenous opioid system. Of course, there are no
opioid-knockout subjects to test whether they respond to
placebo or not. However, data indicate that the opioid system
possibly vary in different subjects.48 Although this finding
may have different causes, genetic factors are probably highly
involved. In line with this suggestion one recent study has
indicated that the COMT gene is directly involved in regulat-
ing the opioid system and the functionality of the opioid
system in human subjects.49 In our placebo study, we crudely
divided the subjects in placebo responders and placebo non-
responders. We then compared the activations elicited by the
opioids (ie, remifentanil) and observed that the placebo re-
sponders activated the rACC whereas the nonresponders did
not. This analysis was powerful because we specifically stud-
ied the opioid response (and not placebo response) in pla-
cebo responders versus. nonresponders. The results are in
line with a more effective opioid system in the placebo re-
sponders. However, this subject sample was very small and
should be repeated in a larger subject sample.
Conclusion
Recent imaging studies have started to disclose a functional
anatomical relationship between the opioid and placebo pro-
cesses in the human brain. An emerging view suggests that a
complex network in the brain is underlying the placebo re-
sponse (Fig. 4), consisting of both opioid rich regions in ACC
and insula (involved in subprocesses of the placebo effect
such as attentional modulation and emotional awareness),
but also regions not activated by opioids such as the orbito-
frontal cortex (involved in the processing of expectation).
This network induces top-down control of a powerful opioid
network in the brainstem. Of course, other regions also may
be involved in the placebo process, eg, the dorsolateral pre-
frontal cortex is probably involved in short-term memory
holding the nonemotional context supporting the placebo
response on-line. Another region possibly belonging to this
network is the amygdala because it is involved in a similar
opioid-dependent control of the brainstem in the fear re-
sponse. In a near future, displacement studies of the opioid
receptor system will further show whether the opioid net-
work may be directly involved in the placebo response.
Moreover a combination between genetic and imaging stud-
ies may indicate whether different genotypes affecting the
opioid system also affects the opioid phenotype and thereby
the placebo response.
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