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The Journal of Neuroscience, May 1, 1999, 19(9):3639-3648
Somatotopic Activation of Opioid Systems by Target-Directed
Expectations of Analgesia
Fabrizio
Benedetti,
Claudia
Arduino, and
Martina
Amanzio
Department of Neuroscience and Center for the Neurophysiology of
Pain, University of Torino Medical School, 10125 Torino, Italy
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ABSTRACT |
We induced specific expectations of analgesia on four different
parts of the body to understand how endogenous opioid systems are
activated by expectancies. The left hand, right hand, left foot, and
right foot were simultaneously stimulated by means of a subcutaneous
injection of capsaicin, which produces a painful burning sensation.
Specific expectations of analgesia were induced by applying a placebo
cream on one of these body parts and by telling the subjects that it
was a powerful local anesthetic. In such a way, expectancy of the
anesthetic effect was directed only toward the part on which the
placebo cream was applied. We found that a placebo analgesic response
occurred only on the treated part, whereas no variation in pain
sensitivity was found on the untreated parts. If the same experiment
was performed after an intravenous infusion of the opioid antagonist
naloxone, this highly spatial-specific placebo response was totally
abolished, indicating that it was completely mediated by endogenous
opioid systems. These findings show that a spatially directed
expectation of pain reduction is capable of inducing a specific effect
only on the part of the body which is the target of the expectation.
Most important, this specific effect is mediated by endogenous opioids, indicating that placebo-activated opioids do not act on the entire body
but only on the part where expectancy is directed. This suggests that a
highly organized and somatotopic network of endogenous opioids links
expectation, attention, and body schema.
Key words:
analgesia; pain; capsaicin; placebo; opioid systems; expectation; attention; body schema
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INTRODUCTION |
Several lines of evidence indicate
that some types of placebo activate endogenous opioid systems (Levine
et al., 1978 ; Grevert et al., 1983; Levine and Gordon, 1984; Benedetti
et al., 1995; Benedetti, 1996; Benedetti and Amanzio, 1997), although
nonopioid mechanisms can play an important role in some situations
(Gracely et al., 1983; Grevert et al., 1983). Fields and Levine (1984) analyzed the different psychological and/or environmental circumstances that might determine whether the placebo response has an opioid component. Recently, we have elucidated, at least in part, some of
these circumstances (Amanzio and Benedetti, 1999). In fact, in
accordance with previous studies (Fields and Levine, 1984; Voudouris et
al., 1990; Fields and Price, 1997; Montgomery and Kirsch, 1997; Price
and Fields, 1997), we showed that a placebo analgesic response can be
elicited by expectation cues and/or conditioning. We found that
expectation-induced placebo analgesia was associated with opioid
activation, whereas conditioning-induced placebo analgesia was mediated
by specific neurochemical pathways, depending on the drug used for
conditioning (Amanzio and Benedetti, 1999).
Although these studies clarify some of the circumstances necessary for
the activation of opioid systems, we do not know how these endogenous
opioids are released. In other words, the problem is to understand how
expectancies activate endogenous opioids and where the
expectation-activated opioids are released within the CNS. Are they
released throughout the brain, thus affecting the entire body, or
rather do they show a high-order organization? At least two
possibilities can be envisaged. First, endogenous opioids could act as
modulators and/or hormones throughout the nervous system, thus
affecting pain sensitivity and responsiveness of the entire body.
Second, the activated opioids could act at a more local level, for
instance, as mediators or transmitters of a specific neuronal
circuitry. In this second case, we should expect no change of pain
sensitivity on the entire body. Interestingly, Montgomery and Kirsch
(1996) showed that specific expectancies may produce specific placebo
responses. These authors found that some types of placebo analgesia
cannot be explained by mechanisms that would affect the entire body
(e.g., release of opioids throughout the nervous system). In fact, by
administering a placebo in the guise of a local anesthetic on one part
of the body, there were no changes in pain responsiveness on the other parts.
Taking into account these considerations, the present study was aimed
at analyzing (1) whether endogenous opioids are activated by specific
expectations, such as the expectancy that the left hand, but not other
parts of the body, will be less sensitive to pain, and (2) whether the
activated endogenous opioids affect only the part of the body where the
expectation is directed or, rather, the entire body. In such a way, we
could understand whether the placebo-activated opioids act throughout
the nervous system or are confined to specific neuronal networks.
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MATERIALS AND METHODS |
Subjects. A total of 173 subjects participated in the
study after they signed a written informed consent in which the
experimental procedure was described and the use of subcutaneous
capsaicin and intravenous naloxone was explained in detail. Each
subject underwent a clinical examination in which the electrocardiogram was recorded. All subjects with heart problems were eliminated from the
study. Many subjects reported a previous experience with analgesics,
both opioids and nonopioids, for different types of pathological
conditions, such as headache and surgery. All experimental procedures were conducted in conformance with the policies and principles contained in the Declaration of Helsinki. The 173 subjects were subdivided into six groups, whose characteristics are shown in
Table 1. The ratio of males/females, age,
and weight did not differ among the different groups.
Pain stimuli. Pain was induced experimentally by means of a
subcutaneous injection of 10 µg of capsaicin (8-methyl
N-vanillyl 6-nonamide) (Fluka, Neu-Ulm, Germany) in 10 µl
of a polyoxyethylene(20)sorbetan monooleate (Tween 80) saline vehicle.
The injection of 10 µg of capsaicin produces a painful burning
sensation reaching a peak within the first minute and lasting 9-12 min
(LaMotte et al., 1991). The capsaicin was injected simultaneously into
the dorsal side of the left hand, right hand, left foot, and right
foot. To do this, a 30 gauge needle was inserted subcutaneously and connected to a catheter, which, in turn, was connected to an infusion pump (Fig. 1). The needles and the
catheters were filled previously with the capsaicin solution. However,
to avoid capsaicin emission during the subcutaneous insertion of the
needle, the needle was filled only partially, leaving 10 µl of empty
space in proximity to the tip. Simultaneous injection of capsaicin
under the skin of the hands and feet was assured by the infusion pump,
which was programmed to deliver 20 µl (10 µl of the empty part
of the needle plus 10 µl of the filled part). In such a way, the
injection of the 10 µl of capsaicin was performed in ~500 msec.
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Figure 1.
Experimental setup. Four subcutaneous needles,
which are filled with capsaicin, are inserted under the skin of the
dorsal side of both hands and both feet and connected to an infusion
pump. The four electrodes are used to signal on which part of the body
the subjects had to focus their attention and to judge capsaicin pain
intensity. Naloxone was administered through the intravenous
line.
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Experimental design. The experiments were performed
according to a randomized double-blind design in which neither the
subject nor the experimenter knew what drug was administered. This was true for both naloxone and the local anesthetic (see below), so that we
were completely blind in all experimental procedures. The subjects
reclined on a bed, and a needle was inserted into a vein of the right
arm (Fig. 1). The needle was connected to a line, 1 m long,
through which a slow infusion of 5% glucose solution was administered.
The intravenous line reached a screen behind the subject's bed, so
that hidden injections could be performed by the experimenter.
The following procedure was used in all 173 subjects. After the
simultaneous injection of capsaicin into the hands and feet, the
subjects had to judge the time course of pain on these four body parts
for the first 15 min. To do this, four silver-chloride electrodes were
positioned on the two wrists and the two ankles (Fig. 1) and connected
to a stimulator and a constant current unit, thus avoiding the
variability of skin-electrode impedance and warranting constant
electrical stimuli throughout the experiment. Starting from 21 sec
before each minute, a mild electric shock was delivered every 7 sec
sequentially on the left hand, right hand, left foot, and right foot
(Fig. 2). These stimuli were used to
signal on which part of the body the capsaicin pain had to be judged.
For example, when the shock was delivered to the left hand, the
subjects had to judge the capsaicin burning sensation on the left hand,
when the shock was delivered to the right foot they had to judge
capsaicin pain on the right foot, and so forth. Both hands and both
feet were tested for all the first 15 min after capsaicin injection
(Fig. 2). The order of stimulation on the hands and feet was changed at
random every minute. Pain intensity was judged according to a numerical
rating scale (NRS), ranging from 0 indicating no pain to 10 indicating
unbearable pain.
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Figure 2.
Experimental design. Starting from time 0, the
same design was used for all 173 subjects. In contrast, they were
subdivided into six groups that received different treatments at 15 and
10 min before time 0.
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The data from every subject were stored in a computer according to a
polar coordinate system subdivided into four quadrants. The upper
left quadrant represented the left hand, the upper right the right
hand, the lower left the left foot, and the lower right the right foot
(Fig. 3). The angular coordinates
represented the time (in minutes) from capsaicin injection and, because
each quadrant had an amplitude of 90° and the pain course was
analyzed for 15 min, each minute had an amplitude of 6°. The distance
from the center of the polar system represented the pain intensity
according to the NRS scores. An example taken from three different
subjects is shown in Figure 3 (see the details in Results). For
instance, the pain course of the right hand of the subject in Figure
3A was represented by a decrease of pain intensity (decrease
of the distance from the center), starting from the first through the fifteenth minute (from 0 through 90°).
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Figure 3.
Data from three representative subjects in polar
coordinate systems. The subject in A belongs to the
natural history group; thus, he did not receive any treatment. The four
quadrants represent the four different parts of the body. For each
quadrant, the pain time course is shown in which the distance from the
center represents pain intensity and the angular coordinates represent
the minutes after capsaicin injection. The first minute after capsaicin
injection is shown for each quadrant. The subject in B
was treated with a placebo cream on the left hand
(underlined), so that expectation of analgesia was
directed to the left hand. Accordingly, a placebo pain reduction
occurred specifically on the left hand. The subject in C
was treated with a placebo cream on the right hand and left foot
(underlined), so that expectation of analgesia was
directed to the right hand and left foot. Accordingly, a placebo pain
reduction occurred specifically on the right hand and left foot.
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Although this procedure was used in all subjects, they received
different treatments before capsaicin injection (Fig. 2). Group 1 received a hidden intravenous injection of saline (NaCl 0.9%) 15 min
before the subcutaneous injection of capsaicin (natural history group).
Group 2 received a hidden intravenous injection of naloxone (Crinos,
Como, Italy) at a dose of 0.14 mg/kg in sterile solution of NaCl 0.9%
(infusion rate, 0.1 ml/sec; total infusion time, ranging from 180 to
240 sec) (hidden naloxone group). This group was used to assess whether
naloxone per se affected the burning pain sensation induced by
capsaicin. In Groups 1 and 2, naloxone and saline were administered
according to the double-blind design.
In Group 3, a neutral cream (a mixture of oil of thyme and water) was
applied around the subcutaneous needle of the left hand 10 min before
capsaicin injection (Fig. 2). These subjects were told that the cream
was a potent local anesthetic reducing the burning sensation of
capsaicin. A hidden intravenous saline injection was performed 15 min
before the injection of capsaicin. Group 4 received the same treatment
as Group 3, but a hidden intravenous injection of naloxone (0.14 mg/kg)
was performed 15 min before the capsaicin injection (Fig. 2). Groups 5 and 6 were treated as groups 3 and 4; however, the placebo cream was
applied to the right hand and left foot (Fig. 2). To apply the neutral
cream according to a double-blind design, in 20 additional subjects (five for each group), we applied a lidocaine 5% cream, which really
anesthetized the skin around the subcutaneous needle.
Assessment of pain thresholds and allodynia. Beside the time
course of capsaicin pain, we also assessed the variations of pain
threshold in the capsaicin-induced allodynia. To do this, we used
electrical stimulation. At the end of the experimental procedure
described previously, the subcutaneous needles were taken out, and the
four electrodes were positioned on the skin where capsaicin had been
injected. The diameter of the electrodes was 6 mm. Pain thresholds on
the hands and the feet were assessed at 30 and 120 min after capsaicin
injection. To do this, the stimulator delivered one stimulus per
second, and the subjects had to adjust the stimulus intensity by using
a hand-grip, until a painful electrical stimulus was perceived. It
should be remembered that the electrical stimuli were delivered through
a constant current unit, thus avoiding the variability of
skin-electrode impedance. In such a way, pain thresholds were expressed
in milliamperes. The subjects assessed their pain thresholds
sequentially on the four parts of the body, and the sequence of pain
threshold assessments on both hands and both feet was changed at random
in each subject and each group. These pain thresholds were compared
with the normal thresholds, which had been measured before starting the
experiment and before inserting the subcutaneous needles. The
variations of pain threshold in capsaicin-induced allodynia were
expressed as the percentages of the threshold of the preinjection
controls (see Fig. 7).
Statistical analysis. The differences between and within
treatments were tested by means of the ANOVA, followed by the
Newman-Keuls multiple range test for multiple comparisons. The data
from single subjects were transformed from the polar coordinate system
to the classic cartesian coordinates to analyze means and SDs of a
single group. In addition, the response of each subject was expressed
as the area under the curve, which was calculated according to the
triangulation method of the study by Winter and Flataker (1949). The
data are presented as mean ± SD. Differences were considered to
be statistically significant at p < 0.05.
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RESULTS |
Analysis of the data from single subjects
To see the outcome of a single subject at a glance during
the experiment, the polar coordinate system was displayed on the computer screen. In such a way, the results for a single subject could
be inspected in real time. Figure 3 shows three examples taken from
three representative subjects; each polar system was taken directly
from the computer screen. The subject in A belongs to the
natural history group and shows a pain time course that is equal on
both hands and both feet. The subject in B received the
placebo cream on the left hand, so that a reduction of pain was found
specifically on the left hand. The subject in C received the
placebo cream on the right hand and the left foot, so that pain
reduction occurred specifically on the right hand and left foot.
The following data and statistical analyses within and between groups
were obtained by transforming the polar coordinate systems of all
subjects into cartesian coordinates.
The natural history of capsaicin pain
The natural history of the pain induced by capsaicin (group 1) is
shown in Figure 4A for
both hands and both feet. The statistical analysis of the areas under
the curves is shown in Table 2 in which
it can be noted that the ANOVA on the right represents the analysis
within a single group, whereas the ANOVA at the bottom represents the
analysis between the two groups for both the hands and the feet. It can
be seen that no significant difference in pain time course was found
between the four parts of the body, as shown by the analysis within
group 1 of Table 2. The consistency of the four pain time courses in
the same group represents an important starting point to unravel
possible differences on hands and feet.
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Figure 4.
A, Natural history of the pain
induced by capsaicin on the hands and feet. B, Same as
in A, but these subjects received a hidden injection of
naloxone. Note that naloxone did not affect the time course of pain.
The statistical analysis of the areas under the curve is shown in Table
2.
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The natural history was not modified by an intravenous dose of 0.14 mg/kg naloxone (group 2), indicating that naloxone per se did not
affect this type of experimental pain. Figure 4B
shows that the hidden naloxone did not produce differences compared with the natural history. This is better evidenced by the statistical analysis of Table 2 in which no significant differences were found
within group 2 and between groups 1 and 2.
Hand-directed expectancy of analgesia
When the placebo cream was applied to the left hand, expectation
of analgesia was specifically directed to the left hand (group 3). In
this case, we observed a clear-cut placebo effect only on the left
hand, whereas the other hand and the feet were unaffected (Fig.
5A). In fact, the response to
capsaicin of the left hand, expressed as the area under the curve, was
significantly smaller than the natural history
(F(1,71) = 35.5; p < 0.001). In
contrast, no difference between group 3 and the natural history was
found for the right hand (F(1,71) = 2.57;
p = 0.114), left foot (F(1,71) = 1.94; p = 0.168), and right foot
(F(1,71) = 0.48; p = 0.492). Table 3 shows the analysis within group
3; it can be seen that the ANOVA on the right and the Newman-Keuls
multiple range test (q coefficient) indicate a significant
difference between the left hand and the other parts of the body.
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Figure 5.
The effects of the application of a placebo cream
on the left hand. The specific expectation of analgesia on the left
hand produced a placebo effect only on the left hand and not on the
other parts of the body (A). This highly specific
placebo effect was completely blocked by naloxone
(B). The broken lines show the
natural histories of Figure 4A. The statistical
analysis of the areas under the curve is shown in Table 3.
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If the placebo cream was applied to the left hand of the subjects who
had previously received intravenous naloxone (group 4), no placebo
effect was found (Fig. 5B). In fact, no difference in the
areas under the curve was found between group 4 and the natural history
for the left hand (F(1,73) = 0.11;
p = 0.745), right hand (F(1,73) = 0.32; p = 0572), left foot
(F(1,73) = 2.43; p = 0.123), and
right foot (F(1,73) = 0.1; p = 0.755). Table 3 shows that no difference was found within group 4. In
addition, the analysis between the two groups 3 and 4 showed a
significant difference only on the left hand. Therefore, the specific
placebo effect on the left hand, which was induced by the
spatial-specific expectation of analgesia on the left hand, was blocked
by naloxone.
It should be noted that the subjects who received the lidocaine cream
to allow the double-blind design showed a strong analgesic effect only
on the left hand in both groups 3 and 4. In fact, in these subjects,
the areas under the curve were the following. In group 3, it was
8.4 ± 6.3 on the left hand, 41.3 ± 15.8 on the right hand,
44.8 ± 17.9 on the left foot, and 39.8 ± 18.3 on the right
foot. In group 4, it was 13.3 ± 9.7 on the left hand, 45.1 ± 16.9 on the right hand, 40.5 ± 16.7 on the left foot, and 42.6 ± 17 on the right foot.
Hand- and foot-directed expectancies of analgesia
If the placebo cream was applied on one hand and one foot,
expectation of analgesia was specifically directed to two parts of the
body. When the placebo was applied to the right hand and left foot
(group 5), we observed a placebo effect only on these two body parts
(Fig. 6A), as shown by
the significant difference of the area under the curve with respect to
the natural history (F(1,70) = 39.0;
p < 0.001 for the right hand and
F(1,70) = 22.05; p < 0.001 for
the left foot). No difference was found between group 5 and the natural
history for both the left hand (F(1,70) = 0.01;
p = 0.979) and the right foot
(F(1,70) = 0.41; p = 0.523). The
ANOVA and the Newman-Keuls test within group 5 showed a significant difference between the treated parts (right hand, left foot) and the
untreated parts (left hand, right foot) (Table
4).
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Figure 6.
The effects of the application of a placebo cream
on the right hand and left foot. The specific expectations of analgesia
on the hand and foot produced specific placebo effects on the right
hand and left foot, whereas the other two parts of the body were
unaffected (A). These specific placebo effects
were completely blocked by naloxone (B). The
broken lines show the natural histories of Figure
4A. The statistical analysis of the areas under
the curve is shown in Table 4.
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In this case also, the previous infusion of naloxone (group 6) blocked
completely the two specific placebo effects (Fig.
6B). In fact, the responses to capsaicin, expressed
as the area under the curve, of the left and right hand and left and
right foot did not differ from the natural history
(F(1,75) = 2.51; p = 0.117; F(1,75) = 0.07; p = 0.797; F(1,75) = 0.45; p = 0.503; F(1,75) = 0.05; p = 0.826, respectively). No difference was found within group 6, and the
analysis between groups 5 and 6 revealed a significant difference only
for the right hand and left foot (Table 4). Therefore, in this case
also, the specific placebo effects on the right hand and left foot,
which were induced by spatial-specific expectancies, were completely
blocked by naloxone.
The subjects who received the lidocaine cream to allow the double-blind
design showed a strong analgesic effect only on the right hand and left
foot in both groups 5 and 6, as shown by the following areas
under the curve. In group 5, the area under the curve was 40.9 ± 15.9 on the left hand, 9.1 ± 7.1 on the right hand, 11.3 ± 7.8 on the left foot, and 42.4 ± 17.6 on the right foot. In group
6, it was 43.8 ± 18.1 on the left hand, 12.9 ± 8.4 on
the right hand, 15.6 ± 9 on the left foot, and
39.7 ± 17.4 on the right foot.
The effects of placebo on capsaicin-induced allodynia
The placebo affected not only the time course of capsaicin pain
but also the pain thresholds on the cutaneous areas where capsa- icin had been injected. At 30 min after capsaicin
injection, the percentage reduction in pain threshold was much smaller
on those parts of the body where the placebo cream had been applied. Figure 7 and Table
5 show that allodynia was significantly
less pronounced at 30 min on the left hand in group 3 (Fig.
7C) and on the right hand and left foot in group 5 (Fig.
7E). The Newman-Keuls multiple range test showed that the
pain threshold of the left hand in group 3 was higher at 30 min
compared with all the other parts of the body (Table 5, q
coefficient). Similarly, in group 5, the pain threshold was higher on
the right hand and left foot compared with the left hand and right
foot. In all the other groups, no significant difference was found at
30 min. When the assessment of allodynia was performed 120 min after
capsaicin injection, no significant difference was present in all
groups (Fig. 7, Table 5). Thus, allodynia was specifically affected by
the placebo cream at 30 min after capsaicin injection, whereas no
placebo effect was found at 120 min.
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Figure 7.
Percent of preinjection control pain threshold at
30 and 120 min after capsaicin injection in all experimental groups. No
significant differences can be observed in A,
B, D, and F. In contrast,
in C and E, the black
columns represent those parts of the body where the placebo
cream was applied and where pain thresholds result to be significantly
higher compared with the other parts of the body. LH,
Left hand; RH, right hand; LF, left foot;
RF, right foot.
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Table 5.
Percent of preinjection control pain threshold at 30 and
120 min after capsaicin injection in all experimental groups
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The subjects who received the lidocaine cream did not show a decrease
of pain thresholds at both 30 and 120 min. The percentages of
preinjection control pain threshold were 95.8 ± 14 at 30 min and
103.2 ± 15.4 at 120 min on the left hand in group 3; 90.5 ± 15 at 30 min and 96.4 ± 15.7 at 120 min on the left hand in group
4; 101.1 ± 13.9 and 100.4 ± 16.2 at 30 min on the right hand and left foot respectively, and 104 ± 15.5 and 99.6 ± 16.3 at 120 min on the right hand and left foot, respectively, in group 5; 96.7 ± 13.7 and 95.9 ± 16.4 at 30 min on the right hand
and left foot, respectively, and 98.9 ± 14.9 and 100.9 ± 16.1 at 120 min on the right hand and left foot, respectively, in group 6.
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DISCUSSION |
Two important findings emerge from this study. First, a placebo
response occurs only on the part of the body where expectation is
directed, indicating that the underlying mechanisms do not affect the
entire body. Second, this highly specific placebo response is mediated
by opioid systems, indicating that the activated endogenous opioids do
not act throughout the nervous system but only on those neural circuits
linking specific expectations to specific placebo responses.
The experimental procedure we used was aimed at assessing capsaicin
pain simultaneously on four parts of the body. To do this, we performed
several pilot experiments and found that the subcutaneous injection of
capsaicin was an adequate pain stimulus for the following reasons.
First, the pain burning sensation was very localized, so that a shift
of attention from one part of the body to another was easily
accomplished. Second, it lasted ~12-15 min, which represents a
necessary condition to elicit a placebo response. In fact, brief stimuli (few seconds) are usually unaffected by placebos (Price, 1988;
Price and Fields, 1997). Third, we used a small dose compared with
previous studies (e.g., LaMotte et al., 1991), so that a strong but
bearable burning sensation was produced. Fourth, the infusion pump
permitted the simultaneous injection of capsaicin. In contrast, in
pilot experiments, we found that it is very difficult to produce
simultaneous ischemic pain on hands and feet by means of the tourniquet
technique. As far as the judgments of pain are concerned, it should be
pointed out that, for each minute after capsaicin injection, the
subjects judged the four pain sensations in 21 sec, thus allowing
almost concurrent pain ratings on four different body parts. Despite
this relatively short period of time, a 7 sec interval was allowed for
each pain judgment, and, usually, most of the subjects
reported their pain scores 3-4 sec after the electric signal.
That this procedure is reliable is demonstrated by the
consistency of the pain time course on hands and feet in the
natural history group. These data were also confirmed by the assessment
of the pain thresholds and allodynia, which clearly show a
spatial-specific placebo analgesic effect. In this regard, it is worth
emphasizing that, to our knowledge, this is the first study showing a
placebo effect on allodynia.
Taking into account these methodological considerations, our data
are in agreement with the findings by Montgomery and Kirsch (1996), who
showed that some types of local placebo responses cannot be explained
by mechanisms affecting the entire body. To reconcile their results
with the opioid-mediated placebo effect, Montgomery and Kirsch (1996)
and Kirsch (1997) hypothesized that the activation of endogenous opioid
systems might occur when placebos are presented as general analgesics,
not when placebos are presented as local analgesics. We would like to
point out that our study was initially conceived on the basis of this
hypothesis, which suggests that different verbal instructions either do
or do not activate endogenous opioid systems. Very interestingly, we
found that the very specific placebo effects, described by Montgomery and Kirsch (1996) and analyzed in detail in the present study, are
mediated by endogenous opioids, indicating that opioid systems can be
activated by both general and local placebos.
How can a local and specific placebo response be explained in terms of
endogenous opioid activation? First of all, we have to consider that a
placebo response may be a result of either cognitive or conditioning
mechanisms or both, although other theories have been proposed (for
review, see Wall, 1994; Benedetti and Amanzio, 1997). In the first
case, expectations and beliefs of analgesia interact with opioid
systems to influence the pain pathways (Fields and Price, 1997; Price
and Fields, 1997; Amanzio and Benedetti, 1999). In the second case, the
placebo response is a learning phenomenon in which previous experience
with analgesics and analgesia plays a crucial role (Batterman and
Lower, 1968; Laska and Sunshine, 1973; Wickramasekera, 1985; Voudouris
et al., 1989, 1990; Benedetti et al., 1998; Amanzio and Benedetti,
1999). However, it is worth stressing that it is not always easy to
differentiate between expectation and conditioning. For example,
Montgomery and Kirsch (1997) showed that placebo analgesia can result
from conditioning but is actually mediated by expectancy. In other
words, conditioning leads to the expectation that a given event will
follow another event, and this occurs on the basis of the information
that the conditioned stimulus provides about the unconditioned stimulus (Rescorla, 1988; Montgomery and Kirsch, 1997). However, a very recent
study shows that a real conditioning may occur via opioid receptors in
placebo respiratory depression, a situation in which expectancy appears
not to be involved (Benedetti et al., 1999). On the basis of these
considerations, it is likely that both cognitive and conditioning
mechanisms are involved in placebo analgesia in different psychological
states and in different circumstances.
The present study adds one more psychological parameter to the placebo
effect, which is the spatially directed expectancy. Although a previous
conditioning with analgesics cannot be ruled out (several subjects had
a previous experience with analgesics), the spatial dimension of
expectation warrants that a cognitive component (i.e., spatial
attention) must be present. This spatial attention (or spatially
directed expectation) appears to be crucial for the activation of
specific opioid systems. These findings lead to some important
conclusions. First, if expectation is directed to a part of the body,
placebo analgesia occurs only on that part, as already demonstrated by
Montgomery and Kirsch (1996). Second, this spatially directed
expectation implies that attentional mechanisms must be involved.
Third, the internal representation of the body (body schema), with its
organization and topography, must be the target of the
expectancy-mediated placebo analgesic effect. Fourth, all the observed
specific placebo effects are mediated by endogenous opioids. Fifth, the
effects of these opioids are specifically directed to those neural
representations of the body, which are the focus (attention) of the expectations.
Reasoning in this way, a nonspecific release of endogenous opioids
throughout the nervous system cannot explain the findings of our study.
Rather, a highly organized network of opioid pathways and/or receptors
appears to link expectation, attention, and body schema, according to
the model shown in Figure 8. Expectation of analgesia can be directed, via attentional mechanisms, to different spatial loci of the body. This complex network activates specific opioid subsystems which, in turn, act only on those parts of the body
that are the targets of expectation. Although this model is necessarily
speculative, the basic underlying principle appears to be the
topographic link between spatially directed expectancies and opioid
systems. In other words, spatial-specific expectations have their own
organization that is maintained at the level of the endogenous opioid
systems.
View larger version (26K):
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|
Figure 8.
Model explaining the findings of the present
study. Spatial-specific expectations of analgesia produce
opioid-mediated placebo effects only on those parts where expectations
are directed. To do this, specific expectations activate specific
opioid subsystems which, in turn, interact with specific topographic
representations of the body. This model implies that placebo-activated
endogenous opioids are not released throughout the nervous system but
are arranged in a highly organized network, linking expectancies,
attention, and body schema. +, Excitation;  , inhibition.
|
|
Modulation of pain by different psychological states is widely
recognized, and many studies have focused their attention on brainstem
mechanisms and related descending inhibitory control (Mayer and Price,
1976; Basbaum and Fields, 1978, 1984; Watkins and Mayer, 1982; Fields
and Price, 1997). For example, Fields (1992), Fields and Basbaum
(1994), and Fields and Price (1997) emphasized the role of
psychological factors, such as expectation, attention, and arousal, in
the modulation of periaqueductal gray and the rostral ventromedial
medulla. Most interestingly, Soper and Melzack (1982) showed a
somatotopic organization of the periaqueductal gray in rodents, such
that the stimulation of different loci produced analgesia in different
cutaneous areas. This indicates a high level of anatomical and
functional organization in the periaqueductal gray (Bandler and
Shipley, 1994). All these pain modulatory networks are affected by
opioid peptides, indicating that endogenous opioid systems play an
essential role in the organization of both periaqueductal gray and
rostral ventromedial medulla (Fields and Basbaum, 1994).
Although the present study cannot demonstrate the involvement of
these neural circuits in spatial-specific placebo analgesia, it
certainly suggests a topographic relationship between expectancies and
opioid systems, occurring for example via the somatotopic organization
of the periaqueductal gray. We feel that this finding will help us to
understand not only the mechanisms of pain and the organization of the
opioid systems but also the interactions between complex mental
activities and neurochemical systems.
| |
FOOTNOTES |
Received Nov. 18, 1998; revised Feb. 1, 1999; accepted Feb. 16, 1999.
This work was supported by grants from Ministero dell'Università
e della Ricerca Scientifica e Tecnologica and Consiglio Nazionale delle
Ricerche Coordinate Project on Trigeminal Pain.
Correspondence should be addressed to Fabrizio Benedetti, Dipartimento
di Neuroscienze, Università di Torino, Corso Raffaello 30, 10125 Torino, Italy.
| |
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TOP
ABSTRACT
INTRODUCTION
