Blockade of nocebo hyperalgesia by the cholecystokinin
Fabrizio Benedettia,b,*, Martina Amanzioa,b, Caterina Casadioc, Alberto Oliaroc, Giuliano Maggic
aDipartimento di Neuroscienze, Universita ` di Torino, Corso Raffaello 30, 10125 Torino, Italy
bCIND Center for the Neurophysiology of Pain, University of Torino Medical School, Torino, Italy
cDepartment of Thoracic Surgery, University of Torino Medical School, Torino, Italy
Received 28 October 1996; revised version received 8 January 1997; accepted 15 January 1997
In patients who reported mild postoperative pain, we evoked a nocebo response, a phenomenon equal but opposite to placebo. Patients
who gave informed consent to increase their pain for 30 min received a substance known to be non–hyperalgesic (saline solution) and were
told that it produced a pain increase. A nocebo effect was observed when saline was administered. However, if a dose of 0.5 or 5 mg of the
cholecystokinin antagonist proglumide was added to the saline solution, the nocebo effect was abolished. A dose of 0.05 mg of proglumide
was ineffective. The blockade of the nocebo hyperalgesic response was not reversed by 10 mg of naloxone. These results suggest that
cholecystokinin mediates pain increase in the nocebo response and that proglumide blocks nocebo through mechanisms not involving
opioids. Since the nocebo procedure represents an anxiogenic stimulus and previous studies showed a role for cholecystokinin in anxiety,
we suggest that nocebo hyperalgesia may be due to a cholecystokinin-dependent increase of anxiety.
the Study of Pain. Published by Elsevier Science B.V.
1997 International Association for
Keywords: Nocebo; Placebo; Anxiety; Pain; Cholecystokinin; Proglumide; Naloxone
We have recently demonstrated that placebo analgesia
can be potentiated by the cholecystokinin (CCK) antagonist
proglumide (Benedetti et al., 1995; Benedetti, 1996). Since
placebo analgesia is mediated by endogenous opiates
(Levine et al., 1978a; Grevert et al., 1983; Fields and
Levine, 1984; Levine and Gordon, 1984; Benedetti, 1996)
and proglumide enhances opiate analgesia (Katsuura and
Itoh, 1985; Price et al., 1985; Watkins et al., 1985a; Watkins
et al., 1985b; Lavigne et al., 1989), placebo potentiation by
proglumide suggests a potentiation of an endogenous opioid
system, probably through the blockade of CCK receptors.
Placebo analgesia represents a situation where the admin-
istration of a substance known to be non–analgesic pro-
duces an analgesic response when the subject strongly
believes that pain will decrease. However, the placebo
response is bidirectional, i.e., analgesic and algesic, but
normally the algesic response is disregarded and subjects
reporting pain increase after placebo are labeled as non-
responders (Skrabanek, 1978). To distinguish the pleasing
and salubrious effects of placebo from the noxious effects,
Kissel and Barrucand (1974) introduced the term ‘nocebo’
(see also Hahn, 1985; Wall, 1992). Nocebo hyperalgesia is
therefore a phenomenon opposite to placebo analgesia: the
administration of a substance known to be non-hyperalgesic
produces a pain increase when the subject strongly believes
that pain will increase. In this sense, nocebo, and thus
expectation of pain increase, can be considered an anxio-
genic (fearful and stressful) procedure. In fact, whereas the
placebo procedure represents a positive (hopeful and trust-
inducing) stimulus, the nocebo procedure represents a nega-
tive anxiogenic stimulus where, for instance, verbal stimuli
anticipate a more painful condition.
It is interesting that previous studies in animal models of
anxiety demonstrated the anxiogenic effect of CCK and its
blockade by CCK antagonists (Powell and Barrett, 1991;
Pain 71 (1997) 135–140
1997 International Association for the Study of Pain. Published by Elsevier Science B.V.
* Corresponding author. Tel.: +39 11 670 77 09; fax: +39 11 670 77 08.
Rataud et al., 1991; Singh et al., 1991; Chopin and Briley,
1993; Lydiard, 1994; Van Megen et al., 1994), including
proglumide (Harro et al., 1990; Harro and Vasar, 1991; Van
Megen et al., 1994). CCK is also capable of inducing panic
in humans (De Montigny, 1989; Abelson and Nesse, 1990;
Bradwejn et al., 1990; Bradwejn et al., 1994), an effect
blocked by CCK-B antagonists (Bradwejn et al., 1994). In
addition, CCK has been hypothesized to be implicated in
anticipatory anxiety (Phillipp et al., 1992).
On the basis of the possible involvement of CCK in both
placebo and anxiety and by considering the anxiogenic nat-
ure of the nocebo procedure, the present study was aimed at
investigating the effects of the CCK antagonist proglumide
on nocebo hyperalgesia, in which subjects received an injec-
tion of saline and were told that it produced a pain increase
in a few minutes.
A double-blind randomized study was performed in 180
patients who gave informed consent to increase their pain
for 30 min. The patients underwent video-assisted thoraco-
scopy (VAT), a type of surgery where an optical probe is
inserted into the chest through a small hole of about 1 cm in
diameter. The surgical procedure of all the VATs consisted
of the excision of tissue for diagnostic purposes. After
recovery from anesthesia, most VAT patients complain of
only mild pain. Anesthesia was induced with fentanyl 100–
150 mg i.v. and maintained with a combination of isophur-
ane and oxygen. Paralysis was achieved by means of atra-
curium 30–40 mg and reversed by 1 mg atropine and 2 mg
neostigmine i.v. No additional medications were adminis-
tered if pain was mild. On the basis of a numerical rating
scale (NRS), ranging from 0 = no pain to 10 = unbearable
pain, we considered only patients with a NRS lower than or
equal to 3. If pain intensity was higher, the patients were
discarded from the study and an analgesic treatment with
non-steroid anti-inflammatory drugs (NSAID) was started.
About 1 h after recovery from anesthesia, patients were
treated as follows (Fig. 1): 18 (group 1) received a hidden
injection of saline (1 ml of NaCl 0.9%) performed behind
a screen through an intravenous line (natural history or
no-treatment group); 18 (group 2) received a hidden injec-
tion of 0.05 mg of proglumide (dissolved in 1 ml sterile
NaCl 0.9% and administered in 1 min); 18 (group 3)
received a hidden injection of 0.5 mg of proglumide; 18
(group 4) received a hidden injection of 5 mg of proglu-
mide; 18 (group 5) were given an open injection (in full
view of the patient) of saline and were told that it produced
a pain increase within 30 min (nocebo); 18 (group 6) were
given an open injection of 0.05 mg of proglumide and were
told that it produced a pain increase within 30 min (no-
cebo + proglumide 0.05 mg); 18 (group 7) received an
open injection of 0.5 mg of proglumide and were told
that it produced a pain increase within 30 min (nocebo
+ proglumide 0.5 mg); 18 (group 8) were given an open
injection of 5 mg of proglumide and were told that it pro-
duced a pain increase within 30 min (nocebo + proglumide
5 mg); 18 (group 9) received a hidden injection of 10 mg of
naloxone 10 min before an open injection of 0.5 mg of
proglumide (nocebo + proglumide 0.5 mg + naloxone);
and 18 (group 10) received a hidden injection of 10 mg of
naloxone 10 min before an open injection of 5 mg of pro-
glumide (nocebo + proglumide 5 mg + naloxone). It is im-
portant to point out that the patients of the first four groups
did not know that any injection was performed; in this way,
both the normal course of pain (group 1) and possible
analgesic effects of the three different doses of proglumide
(groups 2, 3, 4) could be tested. In contrast, the patients of
Fig. 1. Experimental design for each group of patients. Pain rating was
assessed before injection (time 0) and 30 min after injection. Groups 9 and
10 received a hidden injection of naloxone 10 min before the open injec-
tion of proglumide.
F. Benedetti et al. / Pain 71 (1997) 135–140
the remaining six groups received an injection in full view
and appropriate nocebo instructions; in this way, the nocebo
response could be studied by means of saline solution
(group 5), proglumide (groups 6, 7, 8), and naloxone
(groups 9, 10). There were no differences in age and weight
among the patients of the different groups (Table 1).
Pain intensity was assessed before the injection and after
30 min. Data are shown as pain intensity difference, that is,
the difference between the NRS score at 30 min after the
injection and the NRS score before the injection. Patients
could give up at any moment and NSAID was administered
at the end of the test if requested.
The differences between and within treatments were
tested by means of the analysis of variance (ANOVA) fol-
lowed by the Newman-Keuls’ multiple range test for multi-
ple comparisons. Data are presented as mean and standard
deviation. Differences were considered to be statistically
significant at P ? 0.05.
The different groups did not show any difference in sex,
age, weight and pain scores soon after surgery, as shown in
Table 1. Therefore, in all groups both hidden and open
injections were performed on the same pain baseline.
We found that the hidden injections of the three doses of
proglumide did not affect pain intensity compared to the no-
treatment group, indicating that proglumide per se had no
analgesic effects and did not interact with the anesthetic
agents (Fig. 2a). In fact, the pain intensity difference was
0.3 ± 0.2 SD in the no-treatment group (group 1), 0.3 ± 0.4
SD in group 2, 0.2 ± 0.3 SD in group 3, and 0.2 ± 0.4 SD in
group 4 (F(3,68) = 0.53, P = 0.661).
If an open injection of saline was performed, a nocebo
effect was observed, as shown in Fig. 2b. It can be seen that
the pain intensity difference was 2.4 ± 1.4 SD, which is
statistically significant compared to the no-treatment
group (F(1,34) = 39.69, P ? 0.005). By administering an
increasing dose of proglumide, an inhibitory effect of the
nocebo response was observed (F(3,68) = 16.26, P ?
0.001). However, the Newman-Keuls’ multiple range test
showed that the dose of 0.05 mg of proglumide was ineffec-
Sex, age, weight and pain scores soon after surgery (mean ± standard
deviation) for all groups of patients
Sex (m/f) Age Weight (kg)Pain scores
51.4 ± 9.2
53.1 ± 7.2
50.5 ± 6.1
56.4 ± 8.7
55.9 ± 9.0
52.7 ± 6.9
50.9 ± 8.5
51.4 ± 6.0
54.3 ± 7.1
54.9 ± 8.2
63.1 ± 9.8
60.9 ± 10.1
57.9 ± 7.4
59.4 ± 9.9
60.3 ± 11.0
56.6 ± 10.6
59.6 ± 9.0
62.4 ± 12.2
58.7 ± 8.7
60.1 ± 11.3
1.94 ± 0.73
1.71 ± 0.88
1.49 ± 1.21
1.90 ± 0.81
1.67 ± 0.91
1.47 ± 1.15
1.97 ± 0.68
1.84 ± 0.90
1.73 ± 0.95
1.53 ± 1.05
Fig. 2. (a): Pain intensity difference, expressed as the difference between
pain intensity at 30 min after the injection and pain intensity before the
injection, for the patients who received the hidden injections of saline and
of three different doses of proglumide. No difference can be seen. (b): Pain
intensity difference for the patients who received the open injections of
saline and of the three doses of proglumide, and the appropriate verbal
nocebo instructions. The no-treatment group is also shown. Note that a
nocebo response is present in the open saline and 0.05-mg proglumide
groups, whereas if the dose of proglumide was increased the nocebo effect
was abolished. (c): Pain intensity difference for the patients who received
10 mg of hidden naloxone 10 min before an open injection of either 0.5 or
5 mg of proglumide. The no-treatment and open saline groups are also
shown. Note that naloxone does not affect nocebo blockade by proglu-
F. Benedetti et al. / Pain 71 (1997) 135–140
tive (NRS = 2.1 ± 1.1 SD), as shown by a non-significant
(q(68) = 1.222) and by a significant difference relative
to the no-treatment group (F(1,34) = 46.66, P ? 0.004).
In contrast, if the dose of proglumide was increased to 0.5
mg and 5 mg, the nocebo response was abolished (pain
intensity difference = 0.5 ± 0.6 SD and 0.6 ± 0.9 SD,
respectively), as shown by the multiple comparisons with
the open saline group (q(68) = 7.739, P ? 0.01 and
q(68) = 7.332, P ? 0.01, respectively). In addition, no sig-
nificant difference was found between these two groups
and the no-treatment group (F(1,34) = 1.8, P = 0.189 and
F(1,34) = 1.91, P = 0.176, respectively).
The hidden injection of 10 mg of naloxone did not have
any effect on the open injection of the two doses of proglu-
mide (Fig. 2c). In fact, 0.5 and 5 mg of proglumide still
produced a blockade of the nocebo response (pain intensity
difference = 0.7 ± 1 SD and 0.7 ± 1.1 SD, respectively;
F(2,51) = 12.47, P ? 0.001). The Newman-Keuls’ test
showed that both 0.5 mg proglumide + naloxone and 5
mg proglumide + naloxone differed significantly from the
open saline (q(51) = 6.118, P ? 0.01 for both doses).
Moreover, the two naloxone groups (groups 9, 10) were
not significantly different from the no-treatment group
(F(1,34) = 2.77, P = 0.105 and F(1,34) = 2.3, P = 0.138,
respectively). In conclusion, naloxone had no effect on the
blockade of nocebo induced by both 0.5 and 5 mg of pro-
These findings show that, in our experimental conditions,
the nocebo hyperalgesic response was blocked by relatively
large doses (0.5 and 5 mg) of the CCK antagonist proglu-
mide compared to the low doses (0.05 mg) necessary to
potentiate morphine analgesia (Baber et al., 1989). In addi-
tion, the blockade of the nocebo response was not mediated
by endogenous opiates since the infusion of naloxone did
not prevent the effects of proglumide. This latter finding is
rather surprising, considering that previous studies showed
that CCK antagonists act mainly through the potentiation of
opioid peptides (Katsuura and Itoh, 1985; Price et al., 1985;
Watkins et al., 1985a; Watkins et al., 1985b; Lavigne et al.,
1989; Wiesenfeld-Hallin et al., 1990; Maldonado et al.,
1993; Noble et al., 1993; Stanfa et al., 1994; Valverde et
al., 1994; Xu et al., 1994). It should also be remembered that
endogenous opioid systems are altered in different painful
conditions, as shown in patients with chronic neurogenic
pain (Almay et al., 1978) and in patients with postoperative
pain increase after naloxone administration (Lasagna, 1965;
Levine et al., 1978b; Levine et al., 1979; Gracely et al.,
1983). In contrast, in the present study, we did not find
any effect of naloxone on nocebo blockade by proglumide,
suggesting that endogenous opioid systems are not altered
in nocebo-induced hyperalgesia. We would like to point out
that we used a high dose of naloxone (10 mg). It is therefore
unlikely that such a dose was too low to be effective, as also
indicated by the effectiveness of 10 mg of naloxone on the
reversal of placebo analgesia (Levine et al., 1978a; Grevert
et al., 1983; Levine and Gordon, 1984; Benedetti, 1996).
Similarly, we injected naloxone 10 min before the open
injections of proglumide because the effects of naloxone
are already present after 30 min (Benedetti, 1996). Thus,
40 min (10 min before + 30 min after the open proglumide)
represents a safe time interval for the effects of naloxone to
Although the effects of proglumide appear to be straight-
forward, several points should be made. As already stated in
our previous studies (Benedetti et al., 1995; Benedetti,
1996), since proglumide has a low affinity for CCK recep-
tors in the brain (Lin and Miller, 1985; Wennogle et al.,
1985), the action of proglumide may also be mediated by
mechanisms other than blockade of CCK receptors. For
example, proglumide could influence the bio-availability
and metabolism of endogenous opiates, or could act by
influencing opioid binding to the receptors (Lavigne et al.,
1989; Benedetti, 1996). However, the present study shows
that these non-specific mechanisms can be ruled out since
the inhibitory action of proglumide on nocebo is not
mediated by opioids. There is also behavioral and electro-
physiological evidence that CCK is blocked by proglumide
in the brain (Chiodo and Bunney, 1983; Suberg et al., 1985;
Watkins et al., 1985a; Watkins et al., 1985b). Moreover, the
results obtained in humans with proglumide (Price et al.,
1985; Lavigne et al., 1989; Benedetti et al., 1995; Benedetti,
1996) are in accordance with those obtained in recent ani-
mal studies by using specific CCK-B antagonists (Wiesen-
feld-Hallin et al., 1990; Maldonado et al., 1993; Noble et al.,
1993; Valverde et al., 1994; Xu et al., 1994).
Since the blockade of nocebo hyperalgesia is not
mediated by opioids, can we hypothesize other mechan-
isms? Of course, the present study cannot answer this ques-
tion. In fact, other neurotransmitters and/or neuromod-
ulators might be involved and we did not test this possibi-
lity. However, it is important to consider the anxiogenic and
stressful nature of the nocebo procedure (patients expect a
more painful condition). In this regard, it is interesting that
proglumide blocks the anxiogenic effects of CCK-4 (Harro
and Vasar, 1991) and caerulein, a CCK-8 agonist (Harro et
al., 1990), indicating a site of action at the level of motiva-
tional and emotional-affective mechanisms. In fact, CCK
has been proposed as an etiologic factor in anxiety since
CCK agonists induce panic attacks in humans and CCK
antagonists show anxiolytic activity (De Montigny, 1989;
Abelson and Nesse, 1990; Bradwejn et al., 1990; Harro et
al., 1990; Harro and Vasar, 1991; Powell and Barrett, 1991;
Rataud et al., 1991; Singh et al., 1991; Chopin and Briley,
1993; Bradwejn et al., 1994; Lydiard, 1994; Van Megen et
al., 1994). CCK was also related to anticipatory anxiety in
marathon runners (Phillipp et al., 1992).
The involvement of CCK in anxiety makes it possible that
F. Benedetti et al. / Pain 71 (1997) 135–140
the action of proglumide on nocebo may be characterized by
a direct effect on pain and/or an indirect effect through
anxiety mechanisms. In other words, since the nocebo pro-
cedure is an anxiogenic situation, nocebo hyperalgesia may
also be due to a CCK-dependent increase in anticipatory
anxiety which, in turn, affects pain perception. Of course,
this speculation needs validation. Therefore, the develop-
ment of new specific CCK-A and CCK-B antagonists for
clinical investigations will be necessary in order to differ-
entiate the direct effectsof CCK on pain perception from the
indirect effects on pain via motivational-affective mechan-
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