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The Journal of Neuroscience, January 1, 1999, 19(1):484-494
Neuropharmacological Dissection of Placebo Analgesia:
Expectation-Activated Opioid Systems versus Conditioning-Activated
Specific Subsystems
Martina
Amanzio and
Fabrizio
Benedetti
Department of Neuroscience and Centro Interuniversitario per la
Neurofisio logia del Dolore Center for the Neurophysiology of
Pain, University of Torino Medical School, 10125 Torino, Italy
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ABSTRACT |
We investigated the mechanisms underlying the activation of
endogenous opioids in placebo analgesia by using the model of human
experimental ischemic arm pain. Different types of placebo analgesic
responses were evoked by means of cognitive expectation cues, drug
conditioning, or a combination of both. Drug conditioning was performed
by means of either the opioid agonist morphine hydrochloride or the
nonopioid ketorolac tromethamine. Expectation cues produced placebo
responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning produced
placebo responses that were completely antagonized by naloxone.
Morphine conditioning alone (without expectation cues) induced a
naloxone-reversible placebo effect. By contrast, ketorolac conditioning
together with expectation cues elicited a placebo effect that was
blocked by naloxone only partially. Ketorolac conditioning alone
produced placebo responses that were naloxone-insensitive. Therefore,
we evoked different types of placebo responses that were either
naloxone-reversible or partially naloxone-reversible or, otherwise,
naloxone-insensitive, depending on the procedure used to evoke the
placebo response. These findings show that cognitive factors and
conditioning are balanced in different ways in placebo analgesia, and
this balance is crucial for the activation of opioid or nonopioid
systems. Expectation triggers endogenous opioids, whereas conditioning
activates specific subsystems. In fact, if conditioning is performed
with opioids, placebo analgesia is mediated via opioid receptors, if
conditioning is performed with nonopioid drugs, other nonopioid
mechanisms result to be involved.
Key words:
pain; placebo analgesia; cognition; conditioning; morphine; nonsteroid anti-inflammatory drugs; endogenous opioids
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INTRODUCTION |
The neurobiology of placebo was born
when Levine et al. (1978) discovered that the opioid antagonist
naloxone inhibits the placebo analgesic response. There are now several
lines of evidence indicating that placebos activate endogenous opioid
systems, thus producing placebo analgesia (Grevert et al., 1983; Fields
and Levine, 1984; Levine and Gordon, 1984; Benedetti et al., 1995; Benedetti, 1996; Benedetti and Amanzio, 1997; Fields and Price, 1997).
However, Gracely et al. (1983) showed that placebo analgesia may also
occur without the involvement of endogenous opioid systems. In
addition, in the study by Grevert et al. (1983) naloxone blocked placebo analgesia only partially, suggesting that both opioid and
nonopioid components play an important role.
The activation of opioid or nonopioid systems represent only the final
pathway of a complex mechanism that is poorly understood. In the
typical paradigm used to produce placebo analgesia, a substance known
to be nonanalgesic (e.g., saline solution) is administered, and the
subject is told that it is a powerful painkiller. At least two theories
have been proposed to explain this phenomenon as the basis for the
activation of endogenous opioids. First, cognitive factors, like
expectation of pain relief, are supposed to trigger the release of
opioids in the CNS (for review, see Benedetti and Amanzio, 1997; Fields
and Price, 1997). Second, a classical conditioning mechanism has been
proposed, in which repeated associations between active analgesics,
pain relief, and therapeutic surroundings produce a conditioned placebo
analgesic response (Wickramasekera, 1985; Voudouris et al., 1989, 1990;
Benedetti and Amanzio, 1997; Fields and Price, 1997; Price and Fields,
1997). In addition, the anxiety theory postulates that placebo
analgesia is caused by a reduction of anxiety (Evans, 1985), whereas
the response-appropriate sensation theory proposes that the global
experience of pain results from a complex internal analysis of
different brain states (Wall, 1993). These theories are not necessarily
in conflict because each of them may represent a different aspect of
the same phenomenon (Wall, 1992).
Therefore, although there is now a general agreement on the involvement
of endogenous opioids in some types of placebo analgesia (ter Riet et
al., 1998), the mechanisms of their activation is not known. As
stressed by Fields and Levine (1984), it is necessary to understand the
conditions and the mechanisms capable to produce naloxone-reversible
and naloxone-insensitive placebo responses. On the basis of Fields and
Levine's considerations, we analyzed different types of placebo
analgesia that were induced by different combinations of expectation
cues and conditioning procedures, and by different opioid and nonopioid
conditioning drugs. In such a way, we could perform a true
neuropharmacological dissection of placebo analgesia into opioid and
nonopioid components and could identify how these neurochemical systems
are related to cognitive and conditioning mechanisms.
Part of this study has been published in abstract form (Amanzio et al.,
1998).
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MATERIALS AND METHODS |
Subjects. A total of 229 subjects participated in the
study after they signed a written informed consent in which the
experimental procedure was described, and the use of morphine,
ketorolac, and naloxone was explained in detail. In particular, they
were told that these drugs were not dangerous and did not produce side
effects at the doses used in the study. Each subject underwent a
clinical examination in which blood pressure and electrocardiogram were recorded. All subjects with heart problems were not allowed to participate in the study. Most of the subjects referred a previous experience with analgesics, either opioids or nonopioids, for different
types of pathological conditions (e.g., headache or previous surgery).
All the experimental procedures were conducted in conformance with the
policies and principles contained in the Declaration of Helsinki. The
229 subjects were subdivided into 12 groups, whose characteristics are
shown in Table 1. It should be noted that
the ratio of males to females, age, and weight did not differ among the
different groups.
Pain stimulus. Pain was induced experimentally by means of
the tourniquet technique. This test produces ischemic pain of the arm
that increases over time (Smith et al., 1966, 1972; Benedetti, 1996).
To avoid variability among different subjects, we induced a quick
increase of pain according to the following procedure. The subject
reclined on a bed, his or her nondominant forearm was extended
vertically, and venous blood was drained by means of an Esmarch
bandage. A sphygmomanometer was placed around the upper arm and
inflated to a pressure of 300 mmHg. The Esmarch bandage was maintained
around the forearm, which was lowered on the subject's side. After
this, the subject started squeezing a hand spring
exerciser 12 times while his or her arm rested on the bed. Each squeeze
was timed to last 2 sec, followed by a 2 sec rest. The force necessary
to bring the handles together was 7.2 kg. This type of ischemic pain
increases over time very quickly, and the pain becomes unbearable after
about 13-14 min (Table 2). A timer was
started after the last squeeze, and the subject stopped the timer when
the pain became unbearable. At this point, the experiment was
discontinued, and the time was recorded. Thus, pain tolerance was
defined as the time from the last squeeze to unbearable pain.
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Table 2.
The left columns show the pain tolerance baseline on
day 1 in all experimental groups and the comparisons with the natural
history group on day 1 (p levels). The right columns
show the pain tolerance on the day after drug administration and its
comparison with pain tolerance on day 1
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Drug administration. All drugs used in the present study
were administered through an intravenous line. Before starting the experimental procedure, a needle was inserted into a vein of the dominant forearm. 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. In
such a way, hidden injections could be performed by the experimenter. Naloxone (Crinos, Italy) was administered at a dose of 0.14 mg/kg in
sterile solution of NaCl 0.9%. The infusion rate (controlled by an
infusion pump) was 0.1 ml/sec for a total infusion time ranging from
180 to 250 sec. The conditioning drugs were morphine hydrochloride and
ketorolac tromethamine. Morphine hydrochloride is an opioid agonist and
was administered at a dose of 0.12 mg/kg in sterile solution of NaCl
0.9%, with an infusion rate of 0.1 ml/sec (total infusion time ranging
from 70 to 100 sec). Ketorolac tromethamine (Formit, Italy) is a
nonsteroid anti-inflammatory drug (NSAID) with no activity on opioid
receptors, and was administered at a dose of 0.43 mg/kg in sterile
solution of NaCl 0.9%, with an infusion rate of 0.1 ml/sec (total
infusion time ranging from 70 to 110 sec).
Experimental procedure. The experiments were performed
according to a randomized double-blind design in which neither the subject nor the experimenter knew what drug was administered. To do
this, either morphine or saline were given on days 2 and 3. Similarly,
either ketorolac or saline were given on days 2 and 3. On day 4, either
morphine or naloxone or saline were administered. To avoid a large
number of subjects, only two or three subjects per group received
saline on days 2 and 3 and morphine or ketorolac on day 4. These
subjects were not included in the study because they were used only to
allow the double-blind design. By using this experimental approach, we
were completely blind to morphine, ketorolac, and naloxone. All drugs
were administered 10 min before inflating the sphygmomanometer cuff,
and the time interval from cuff inflation to the last squeeze was 1 min. Thus, the time interval from drug administration to last squeeze
was the same in all subjects (11 min). The complete experimental
procedure is shown in Figure 1. Group 1 (natural history) was tested with the tourniquet technique for 4 consecutive days without receiving any treatment. Group 2 received a
hidden injection of naloxone performed through the intravenous line
behind the screen on days 2 and 4, to ascertain whether naloxone per se
affected the ischemic pain. It is important to emphasize that this
group did not know that any injection was performed. Group 3 received
an open injection (in full view of the subject) of saline (NaCl 0.9%
solution) on day 2 and was told that it was a powerful painkiller
(placebo with expectation of pain relief). Group 4 received an open
injection of naloxone on day 2 and was told that it was a potent
painkiller (placebo with expectation plus naloxone). Group 5 was
treated with morphine (open injection) on days 2 and 3 (conditioning)
and received an open injection of saline on day 4, believing that it
was morphine (placebo with expectation). Group 6 was treated with
morphine (open injection) on days 2 and 3 (conditioning) and received
an open injection of naloxone on day 4, believing that it was morphine (placebo with expectation plus naloxone). Groups 7 and 8 received the
same treatment of groups 5 and 6. However, the open injections of
saline or naloxone on day 4 were believed to be a neutral nonanalgesic solution (antibiotic) used for sterility purposes; in this case, subjects did not expect any pain relief (placebo without expectation but with previous conditioning). Groups 9-12 were treated as groups 5-8, with the exception that conditioning on days 2 and 3 was performed with the nonopioid ketorolac.
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Figure 1.
Experimental paradigm used in the study to
identify the opioid and nonopioid components of placebo analgesia.
Below each group the experimental condition is specified. No
treatment means that the tourniquet test was performed without
infusion of any drug.
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The verbal instructions used in the different experimental conditions
are reported below. In the conditioning procedures with either morphine
or ketorolac on days 2 and 3, subjects were told that the drugs were
potent analgesics producing a quick pain reduction and, therefore, an
increase of tolerance. On day 4, in the expectation procedure (groups
5, 6, 9, and 10), subjects were told that the drug was the same potent
analgesic used on days 2 and 3. By contrast, in the no-expectation
procedure (groups 7, 8, 11, and 12), subjects were told that the drug
was an antibiotic used "to clean the blood" for the sake of
sterility; thus, these subjects believed that day 4 was not used for
analgesic tests.
It should be noted that the tourniquet test was performed without any
treatment on the first and last days in all groups, and it was used as
a control.
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. In
addition, linear regression analysis was performed by considering the
data from single subjects. Therefore, data are presented as mean ± SD or for single subjects. Differences were considered to be
statistically significant at p < 0.05.
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RESULTS |
The natural history of ischemic arm pain
The natural history group showed no variation of pain tolerance
when the tourniquet test was repeated for 4 consecutive days (F(3,165) = 1.5; p = 0.216),
indicating that the tourniquet technique produces pain tolerances that
remain constant for several days (Fig.
2A). In all groups, the
pain tolerance baseline on day 1 did not differ from the mean value of
the natural history group (Fig. 2B). It can also be
seen in Table 2 that no significant difference was found between each
group and the natural history on day 1. In addition, the post-treatment
control test (either day 3 for groups 2-4 or day 5 for the other
groups) did not differ from the pretreatment control test of day 1 (Table 2). In conclusion, when the tourniquet test was performed
without any treatment (controls), it always produced constant and
consistent results in a range of time of at least 5 d. Therefore,
any departure from this pain tolerance baseline (natural history) can
be viewed as a true placebo effect.
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Figure 2.
Analysis of the natural history of ischemic pain.
A, Means and SDs of the natural history are shown for
group 1 on 4 consecutive days. B, Pain baseline
(mean ± SD) on day 1 in all groups and comparison with the
natural history group on day 1. The horizontal bold line
represents the mean of day 1 shown in A, the
broken lines represent the SD. The statistical analysis
of the natural history is shown in Table 2.
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Opioid-mediated placebo analgesia
Before starting the conditioning procedures, we wanted to test
whether a placebo effect and its reversal by naloxone could be
adequately observed in these experimental conditions. First of all, we
tested whether naloxone per se affects this type of experimental pain.
A hidden injection of naloxone (group 2) on days 2 and 4 did not
produce any variation of pain tolerance compared with days 1 and 3 (F(3,72) = 0.01; p = 0.991)
(Fig. 3A). Then we evoked a
placebo response by injecting saline which the subjects believed to be
a potent painkiller (group 3); a clearcut placebo effect could be
observed compared with days 1 and 3 (F(1,15) = 12.36; p < 0.003) (Fig. 3B). If, however,
the open injection contained naloxone (group 4), no effect could be
observed (Fig. 3C); in fact, no difference was found between
days 2 and 1 (F(1,14) = 4.41; p = 0.054). It is worth noting that, albeit nonsignificant, there was a
tendency for pain tolerance on day 2 to be smaller than on day 1. Therefore, we can conclude that this type of experimental pain (1) is
not affected by naloxone, (2) can produce placebo responses, and (3)
these placebo responses are blocked by naloxone.
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Figure 3.
Expectation-induced placebo analgesia and its
blockade by naloxone. A, A hidden injection of naloxone
on days 2 and 4 (group 2) does not produce any change in pain tolerance
compared with days 1 and 3, indicating that naloxone per se does not
affect this type of experimental pain. B, An open
injection of saline (group 3) produces a placebo analgesic effect. Days
1 and 3 represent preinjection and postinjection controls.
C, An open injection of naloxone on day 2 (group 4)
blocks the placebo effect completely. In fact, pain tolerance on day 2 is equal to preinjection and postinjection controls.
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Conditioning with morphine hydrochloride
When morphine was administered on days 2 and 3, a significant
increase in pain tolerance was found (F(1,12) = 274.46; p < 0.0001 and F(1,12) = 157.25; p < 0.0001, respectively) (Fig.
4A). A saline injection
on day 4, which the subjects believed to be morphine (group 5),
mimicked the morphine responses of the previous days
(F(1,12) = 69.12; p < 0.001),
whereas pain tolerance returned to baseline on day 5 (F(1,12) = 0.03; p = 0.862)
(Fig. 4A). If the same procedure was performed but
naloxone, which was believed to be morphine, was injected on day 4 (group 6), no morphine-mimicking response could be observed
(F(1,13) = 0.09; p = 0.765)
(Fig. 4B). The same procedure was also used in groups
7 (Fig. 4C) and 8 (Fig. 4D). However, the
subjects were told that the injection of day 4 was an antibiotic and,
thus, they did not expect any pain relief. In group 7 (Fig.
4C), a morphine-mimicking response was found after saline
injection on day 4, even if no expectation of pain relief was present
(F(1,13) = 78; p < 0.001),
indicating that the previous morphine conditioning per se was
sufficient to evoke a placebo effect. There was a significant
difference between the placebo effects of groups 5 (Fig.
4A) and 7 (Fig. 4C)
(F(1,25) = 5.5; p < 0.03),
indicating that conditioning plus expectation produces a placebo
response that is larger than conditioning alone. The
conditioning-induced placebo effect was completely blocked by naloxone
(group 8) because no effect was observed after an open injection of
naloxone that the subjects believed to be an antibiotic
(F(1,15) = 0.32; p = 0.580)
(Fig. 4D). It is important to note that pain
tolerance returned to baseline on day 5 in all cases.
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Figure 4.
A, After morphine conditioning on
days 2 and 3, an open injection of saline, which is believed to be
morphine (group 5), mimicks the morphine analgesic response.
B, If an open injection of naloxone, which is believed
to be morphine (group 6), is performed after 2 days of morphine
conditioning, the morphine-mimicking effect is completely abolished.
C, After morphine conditioning for 2 consecutive days,
an open injection of saline, which is believed to be an antibiotic
(group 7), mimicks the morphine response (albeit less than in
A). D, An open injection of naloxone,
which is believed to be an antibiotic (group 8), completely blocks the
morphine-mimicking effect. In all cases, days 1 and 5 represent
preconditioning and postconditioning controls.
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We also performed a linear regression analysis by considering the data
from single subjects. We found a high correlation between the response
to morphine on day 3 and the response to saline on day 4, according to
the rule "the larger the morphine responses, the larger the placebo
responses." The analgesic response to morphine was expressed as
 t, that is, the difference between pain tolerance on days 3 and 1. Similarly, the analgesic response to placebo was
expressed as the difference of pain tolerance on days 4 and 1. This was
true for both groups 5 and 7 (r = 0.627;
t(11) = 2.669; p < 0.025 and
r = 0.855; t(12) = 5.704;
p < 0.001, respectively) (Fig.
5, black circles).
Naloxone disrupted completely this correlation in both groups 6 and 8 (r = 0.187; t(12) = 0.661;
p = 0.521 and r =  0.282;
t(14) = 1.1; p = 0.290, respectively) (Fig. 5, white circles).
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Figure 5.
Relationship between the analgesic response to
morphine on day 3 and the placebo analgesic response on day 4. Each
circle represents the response of a single subject. The
responses are expressed as t, that is, the difference of pain
tolerance between days 3 and 4 and day 1. A, In group 5 (black circles), the larger the morphine response, the
larger the placebo response after a saline injection that is believed
to be morphine. This correlation is completely disrupted by naloxone in
group 6 (white circles). B, Same as in
A but the saline injection is believed to be an
antibiotic (groups 7 and 8).
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In conclusion, the placebo responses induced by morphine conditioning
plus expectation and morphine conditioning alone could be blocked
completely by naloxone.
Conditioning with ketorolac tromethamine
The same procedures used for morphine conditioning and described
above were repeated with the nonopioid ketorolac. Administration of
ketorolac on days 2 and 3 produced strong analgesic responses (F(1,16) = 193.88; p < 0.0001 and F(1,16) = 83.22; p < 0.001, respectively) (Fig.
6A). In both groups 9 (Fig. 6A) and 11 (Fig. 6C), the saline
injection produced ketorolac-mimicking responses (F(1,16) = 68.36; p < 0.001 and
F(1,13) = 28.04; p < 0.001, respectively). If naloxone was administered on day 4 (group 10) and was
believed to be ketorolac (Fig. 6B), the
ketorolac-mimicking response was still present
(F(1,14) = 56; p < 0.001), but
was significantly smaller than the mimicking response of group 9 (F(1,30) = 5.65; p < 0.025).
Therefore, in this case the placebo response was only partially
abolished by naloxone. By contrast, if naloxone was administered on day
4 (group 12) and was believed to be an antibiotic (no-expectation, Fig.
6D), it was completely ineffective in blocking the
conditioning-induced placebo response. In fact, the ketorolac-mimicking response was still present (F(1,13) = 59.47;
p < 0.001).
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Figure 6.
A, After ketorolac conditioning on
days 2 and 3, an open injection of saline that is believed to be
ketorolac (group 9) mimicks the ketorolac analgesic response.
B, An open injection of naloxone, which is believed to
be ketorolac (group 10), blocks the ketorolac-mimicking effect only
partially. C, After ketorolac conditioning for 2 consecutive days, an open injection of saline that is believed to be an
antibiotic (group 11), mimicks the ketorolac response.
D, An open injection of naloxone, which is believed to
be an antibiotic (group 12), is ineffective in abolishing the
ketorolac-mimicking effect. Preconditioning and postconditioning
control tests are shown on days 1 and 5 in all cases.
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The linear regression analysis performed with the data from single
subjects gave the same results (Fig. 7).
A correlation between ketorolac responses on day 3 and placebo
responses on day 4 was present in groups 9 and 11, which received
saline (r = 0.815; t(15) = 5.44;
p < 0.001 and r = 0.645;
t(12) = 2.924; p < 0.015, respectively) and in groups 10 and 12, which received naloxone
(r = 0.580; t(13) = 2.566;
p < 0.025 and r = 0.554;
t(12) = 2.308; p < 0.04, respectively).
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Figure 7.
Relationship between the analgesic response to
ketorolac on day 3 and the placebo analgesic response on day 4. Each
circle represents the response of a single subject. As
in Figure 5, the responses are expressed as t, that is, the
difference of pain tolerance between days 3 and 4 and day 1. A, In group 9 (black circles), the larger
the ketorolac response, the larger the placebo response after a saline
injection that is believed to be ketorolac. This correlation is
maintained after naloxone injection in group 10 (white
circles). B, Same as in A but the
saline injection is believed to be an antibiotic (groups 11 and 12). In
this case, naloxone is completely ineffective in disrupting the
correlation.
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Therefore, the placebo responses induced by ketorolac conditioning plus
expectation were only partially blocked by naloxone, whereas those
induced by ketorolac conditioning alone were naloxone-insensitive.
The naloxone-reversible and naloxone-insensitive components
of placebo
Because of the complex experimental design, a brief summary of the
statistical analysis previously described is reported below. Expectation alone (group 3) produces a placebo response that can be
blocked completely by naloxone (group 4) (Fig.
8A). Conditioning with
morphine plus expectation cues (group 5) produce a placebo effect that
is larger than morphine conditioning alone (group 7); both can be
blocked completely by naloxone (groups 6 and 8) (Fig.
8B). Conditioning with ketorolac plus expectation
cues (group 9) produce a placebo effect that has the tendency
(F(1,29) = 2.92; p = 0.098) to
be larger than ketorolac conditioning alone (group 11). The former can
be blocked by naloxone only partially (group 10), whereas the latter is
completely insensitive to naloxone (group 12) (Fig. 8C).
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Figure 8.
Dissection of placebo analgesia into
naloxone-reversible and naloxone-insensitive components.
A, Expectation-induced placebo analgesia is completely
blocked by naloxone. B, Morphine conditioning plus
expectation produces a placebo response that is totally blocked by
naloxone. Morphine conditioning alone induces placebo responses that,
similarly, are completely blocked by naloxone. C,
Nonopioid ketorolac conditioning plus expectation produces a placebo
response that is only partially antagonized by naloxone. By contrast,
nonopioid ketorolac conditioning alone induces placebo responses that
are completely insensitive to naloxone.
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DISCUSSION |
In the present study we have produced different types of placebo
response that can be totally blocked, partially blocked, or totally
unaffected by naloxone. This indicates that placebo analgesia can be
dissected into opioid and nonopioid components, depending on the
procedure used to induce the placebo response. These findings were
obtained by using a model of experimental pain that has been shown to
be sensitive to morphine (Smith et al., 1966, 1972) and to produce well
measurable placebo responses (Grevert et al., 1983; Benedetti, 1996).
Most important, this type of experimental ischemic arm pain was found
to be unaffected by naloxone (Grevert and Goldstein, 1977, 1978;
Benedetti, 1996), a necessary condition when naloxone is used to study
placebo analgesia. Therefore, the present results are in accordance
with previous investigations, confirming that naloxone per se does not
influence ischemic arm pain (Fig. 3A). In addition, we also
produced an increase of pain tolerance by means of ketorolac, an NSAID
with powerful analgesic activity and no opioid action. It should be pointed out that NSAIDs are known to act at peripheral sites during inflammation by inhibiting the cyclo-oxygenase enzyme necessary for the
conversion of arachidonic acid into prostaglandins (Levine and Taiwo,
1994). However, recently it was shown that NSAIDs have a central site
of action at the spinal level (Malmberg and Yaksh, 1992). Thus,
inflammation is not a necessary condition for the analgesic action of
NSAIDs, and the findings of the present study show that ketorolac is a
powerful analgesic in experimental ischemic arm pain (Fig. 6).
In a previous study (Benedetti, 1996), we observed that the tourniquet
technique induces an increase of pain over time that is variable among
different subjects. To reduce this variability, we inflated the
sphygmomanometer cuff up to 300 mmHg, maintained the Esmarch bandage
around the forearm throughout the test, and used a hand exerciser with
a force of 7.2 kg. These modifications, compared with the study by
Benedetti (1996), produced a quick increase of pain, such that pain
tolerances were reduced and variability decreased. In addition, drugs
were administered 10 min before cuff inflation, so that a long time
interval was allowed for the drug to produce its effects (~25 min; 11 min before the last squeeze plus ~14 min of pain tolerance).
Therefore, by reducing both pain tolerance and variability, and by
maintaining constant the time interval for drug peak effects, we could
obtain homogenous populations of subjects. In addition, the use of
tolerance as a measure of pain needs some considerations. In fact,
tolerance is a complex variable in which the motivational-affective
dimension of pain appears to be more important than the sensory
dimension (Price, 1988). We measured pain tolerance because it has been
shown to be affected by analgesics like morphine (Smith et al., 1966), thus indicating that such a measure of pain can be used to test analgesic drugs. Accordingly, we wanted to see whether placebos produced analgesic-like effects, that is, an increase in tolerance. Even if tolerance measures both the sensory and the
motivational-affective component of pain, as carefully stated by Price
(1988), this is not against our findings.
One of the main findings emerging from this study is that cognitive
factors like expectation appear to trigger endogenous opioid systems in
all cases. When we talk of expectation, we refer to verbal expectation.
In fact, the subjects believed to receive an analgesic, such that they
expected a relief of pain. Although we have not actually measured a
change in expectation, the verbal cues (analgesic or antibiotic) are
clearly directed in two opposite directions: the first increasing, the
second reducing expectation. Unfortunately, we do not know whether in
group 3 (expectation) a previous conditioning occurred (Fig.
8A). In fact, most of the subjects had a previous
experience with either opioids or nonopioids (e.g., headache or
surgery). Nonetheless, the conditioning experiments with morphine and
ketorolac clearly indicate that expectation-induced placebo responses
are mediated by endogenous opioids. For example, it is worth
emphasizing that ketorolac conditioning alone was naloxone-insensitive,
whereas ketorolac conditioning plus expectation was partially
naloxone-reversible (Fig. 8C). This indicates that, by
adding expectation cues, an opioid component comes out.
On the other hand, conditioning-induced placebo responses are not
mediated by endogenous opioids per se but by specific subsystems, depending on the drug used for conditioning (Fig.
9). If an opioid like morphine is used,
conditioning occurs via opioid receptors such that the resulting
conditioned placebo response will be naloxone-reversible. Conversely,
if conditioning is performed with a nonopioid drug like ketorolac, the
resulting placebo response will be naloxone-insensitive. This is
probably caused by the involvement of specific mechanisms during
conditioning. For instance, the NSAIDs, like ketorolac, act at both
peripheral and central sites in the spinal cord (Malmberg and Yaksh,
1992), inhibiting the cyclo-oxygenase enzyme necessary for the
conversion of arachidonic acid into prostaglandins. Therefore, conditioning might occur via these nonopioid pathways. We further propose that, if other analgesics (e.g., the  2 adrenergic receptor agonist clonidine or the tricyclic-type antidepressant amitriptyline) are used for conditioning, other mechanisms may result to be involved (e.g., via adrenergic pathways), thus producing a naloxone-insensitive placebo analgesia (Fig. 9).
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|
Figure 9.
Schematic diagram of the mechanisms activating
endogenous opioid systems and nonopioid systems in placebo analgesia.
The administration of a placebo can trigger both cognitive
(expectation) and conditioning mechanisms. Expectation
activates endogenous opioid systems, whereas conditioning is mediated
by specific mechanisms. If conditioning is performed with opioids,
placebo analgesia is mediated via opioid receptors. However, if
conditioning is performed with nonopioid drugs, other mechanisms result
to be involved. Therefore, placebo analgesia can result to be either
naloxone-reversible or partially naloxone-reversible or, otherwise,
naloxone-insensitive, depending on the procedure used to evoke the
placebo response.
|
|
These findings clarify some previous contrasting studies showing that
placebo analgesia is unaffected (Gracely et al., 1983) or reversed
(Levine et al., 1978; Grevert et al., 1983; Benedetti, 1996) by
naloxone. In fact, if we ignore the strength of the expectation cues
and the previous experience (conditioning) with opioids or nonopioids,
different subjects with different past experiences can be mistakenly
considered to be homogeneous. This issue was first raised by Fields and
Levine (1984), who analyzed the different circumstances that might
determine whether the placebo response has an opioid component. In
particular, Fields and Levine stressed that complex psychological
factors, such as instructions, consent form, remuneration, time of
placebo administration, method of pain rating, site, and cause of pain
may be relevant for the activation of endogenous opioid systems. Thus,
it is not surprising that previous studies found placebo effects that
respond totally, partially, or do not respond at all to naloxone. If,
for example, expectation cues are not adequate, and the subject has
been previously conditioned with nonopioid drugs, the placebo response
is likely to be naloxone-insensitive. By contrast, if the subject had a
previous experience with opioids, and the expectation cues are strong,
the placebo response will result to be naloxone-reversible.
It is interesting that placebo responses occurred even without
expectation of pain relief. In other words, if the subject was
previously conditioned with either morphine or ketorolac, the lack of
expectation cues only reduced but did not prevent the occurrence of a
placebo effect. These findings are in agreement with those by Voudouris
et al. (1990), who showed that conditioned placebo responses can be
obtained without expectancy. Thus, previously conditioned subjects
experience an analgesic effect even if they do not expect it.
Nonetheless, it should be reminded that in a recent work, Montgomery
and Kirsch (1997) showed that placebo analgesia can result from
conditioning but is mediated by expectation. This is consistent with
our findings that, by reducing expectation in conditioned subjects
(belief to receive an antibiotic), the placebo effect results to be
smaller. However, this small residual effect is likely to represent a
sequence effect caused by learning (conditioning), with little or no
involvement of expectation. This notion is supported by a recent study
(Benedetti et al., 1999), showing that a similar conditioning can be
found in placebo respiratory depression, a phenomenon mediated by
endogenous opioids and in which expectation cues are not present.
Several studies showed that conditioning plays an important role in the
placebo response, and this is true for pain, the immune system and, in
general, for pharmacotherapy (Gleidman et al., 1957; Herrnstein, 1962;
Batterman, 1966; Batterman and Lower, 1968; Laska and Sunshine, 1973;
Ader, 1985; Siegel, 1985; Wickramasekera, 1985; Voudouris et al., 1989,
1990; Ader, 1997; Benedetti et al., 1998). Similarly, cognitive and
motivational factors, such as expectation and desire of pain relief,
appear to play an essential role (Fields and Price, 1997; Price and
Fields, 1997). The findings of the present study and the experimental
approach by itself show that cognition and conditioning can be balanced
in different ways during a placebo procedure. This balance is crucial
for the activation of opioid systems or other specific subsystems and
has at least three important implications. First, a complex cognitive
function, like expectation of pain relief, is capable to interact with
neurochemical systems and to produce a specific analgesic effect.
Second, the placebo response depends on past experience, being mediated
by specific subsystems that are likely to be activated during learning. Third, the understanding of the intricate mechanisms linking mental activity and pain will help in planning new therapeutic strategies.
| |
FOOTNOTES |
Received Aug. 28, 1998; revised Oct. 14, 1998; accepted Oct. 21, 1998.
We thank the two reviewers for their important criticisms. They helped
us to improve the article. This work was supported by grants from
Ministero dell'Universitá 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
