Systematic Review and Meta-Analysis

Neurotransmitter systems involved in placebo and

nocebo effects in healthy participants and patients
with chronic pain: a systematic review
Ina Skyta,*, Sigrid J. Lundea, Cathrine Baastrupb, Peter Svenssonc,d, Troels S. Jensene,f, Lene Vasea

Abstract
The investigation of neurotransmitter systems in placebo and nocebo effects has improved our understanding of these phenomena.
Yet, most studies involve healthy participants. Because the pain modulatory system may differ in healthy participants and patients
with chronic pain, it is important to investigate the evidence for neurotransmitter involvement in placebo and nocebo effects in each
of these populations. PubMed, Embase, and Scopus databases, and the Cochrane Library were searched for articles investigating
the endogenous opioid, endocannabinoid, dopaminergic, oxytocinergic, vasopressinergic, and cholecystokininergic (CCKergic)
Downloaded from http://journals.lww.com/pain by BhDMf5ePHKbH4TTImqenVCujjNLp0k9kuDN7KjRmEtpy/5UUtpBbvs5qAmrHmeEn on 01/06/2020

systems in placebo and nocebo effects in pain. Twenty-eight placebo and 2 nocebo studies were included. Vote counting was used
to balance the number of positive vs negative findings. In healthy participants, the endogenous opioid, endocannabinoid, and
vasopressinergic systems were involved in placebo effects, whereas findings on the dopaminergic and oxytocinergic systems were
mixed. In patients with chronic pain, only 4 studies investigated neurotransmitters showing no involvement of the endogenous opioid
system and mixed findings regarding the dopaminergic system. As to nocebo effects, 2 studies suggest that the CCKergic system is
involved in nocebo effects in healthy participants. Overall, research has come a long way in specifying the neurotransmitter systems
involved in placebo effects in healthy participants. Yet, evidence for the involvement of neurotransmitter systems in placebo effects in
patients with chronic pain and in nocebo effects in healthy participants and patients is scarce. Based on the existing evidence, this
systematic review suggests that knowledge obtained in healthy participants may not necessarily be transferred to chronic pain.
Keywords: Placebo and nocebo effects, Pain, Neurotransmitter systems, Healthy participants, Patients with chronic pain

1. Introduction is therefore essential to directly investigate the neurotransmitter

Neurotransmitters, defined as substances that transmit nerve
impulses across a synapse, have been investigated as potential
mediators of placebo and nocebo effects in pain to improve our
understanding of these phenomena and the underlying mecha-
nisms. Most of these studies have been conducted in healthy
participants exposed to experimental pain1,6,10,14,25 or experi-
encing acute postoperative pain.29,40,41 Yet, a current objective in
this research field is to understand how to optimize placebo
effects and minimize nocebo effects in clinical practice,18,38 and it
Sponsorships or competing interests that may be relevant to content are disclosed
at the end of this article.
a
Department of Psychology and Behavioural Sciences, School of Business and
Social Sciences, Aarhus University, Aarhus, Denmark, b Department of Clinical
Biochemistry, Regional Hospital Horsens, Horsens, Denmark, c Section of Orofacial
Pain and Jaw Function, Department of Dentistry and Oral Health, Aarhus University,
Aarhus, Denmark, d Department of Dental Medicine, Karolinska Institutet, Hud-
dinge, Sweden, e Department of Clinical Medicine, Danish Pain Research Center,
Aarhus University, Aarhus, Denmark, f Department of Neurology, Aarhus University
Hospital, Aarhus, Denmark
*Corresponding author. Address: Department of Psychology and Behavioural
Sciences, School of Business and Social Sciences, Aarhus University, Bartholins
Allé 9, 8000 Aarhus C, Denmark. Tel.: 145 8716 5791; fax: 145 8715 0201.
E-mail address: skyt@psy.au.dk (I. Skyt).
Supplemental digital content is available for this article. Direct URL citations appear
in the printed text and are provided in the HTML and PDF versions of this article on
the journal’s Web site (www.painjournalonline.com).
PAIN 161 (2020) 11–23
© 2019 International Association for the Study of Pain
http://dx.doi.org/10.1097/j.pain.0000000000001682
systems involved in placebo and nocebo effects in patients with
chronic pain. The endogenous opioid system has repeatedly
been found to be involved in placebo effects in healthy
participants,14,25,40,41,69 and 2 systematic reviews (one also
a meta-analysis) support this finding.58,65 Studies have also found
involvement of the endocannabinoid,12,47 dopaminergic,60 oxy-
tocinergic,37 and vasopressinergic20 systems in placebo effects
in healthy participants. Furthermore, studies have shown that the
cholecystokininergic (CCKergic) system is involved in nocebo
effects in healthy participants.10,13
Although valuable knowledge can be derived from studies in
healthy participants, it is important to be aware that short-
duration experimental or acute pain in healthy participants differs
from chronic pain in patients. Healthy participants typically have
an intact nociceptive system to modulate pain, whereas chronic
pain involves complex pathophysiology and different mecha-
nisms may be causing the pain.5,43,64 For example, some types of
chronic pain, including neuropathic pain, are related to central
sensitization,43 whereas other types of chronic pain are due to
a disturbed endogenous pain modulatory system.43,64 Moreover,
the psychological components of pain processing, including
negative emotions and cognitions, are often more pronounced in
patients with chronic pain, given that their pain is persistent or
recurrent.54 Therefore, the mechanisms underlying placebo
effects in healthy participants may not necessarily be transferred
to patients with chronic pain.56
Reviews discussing the neurotransmitter systems in placebo
and nocebo effects exist but past reviews have either been

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I. Skyt et al. 161 (2020) 11–23
qualitative7,8,19 or limited to pharmacological studies of the
endogenous opioid system.58,65 Whereas pharmacological
studies have investigated the involvement of neurotransmitter
systems in both placebo1,40,41 and nocebo10 effects, studies on
neurotransmitters involved in placebo effects also include brain
imaging16,49,69 and genetic studies.31 In pharmacological stud-
ies, the involvement of a neurotransmitter system is evidenced by
changes in the magnitude of the placebo or nocebo effect
through antagonism or agonism of the neurotransmitter sys-
tem.10,41,54,63 Functional brain imaging (functional magnetic
resonance imaging, positron emission tomography) can reveal
changes in activity in relevant brain areas (eg, opioid-rich regions)
or in neurotransmission activity.25 Genetic analyses explore the
association between placebo effects and genetic variations (eg,
within the m-opioid receptor gene) and may thereby point to
neurotransmitter systems in placebo effects.31,32 Accordingly, to
obtain a comprehensive understanding of the neurotransmitter
involvement in placebo and nocebo effects, it is of great
importance to systematically summarize the findings across
different methodologies.
This is the first study to systematically review the existing evidence
for the involvement of neurotransmitter systems in both healthy
participants experiencing experimental or acute postoperative pain
and patients with chronic pain. Specifically, this review investigates
the endogenous opioid, endocannabinoid, dopaminergic, oxy-
tocinergic, vasopressinergic, and CCKergic systems in placebo
and nocebo effects. To the best of our knowledge, this encom-
passes the traditional neurotransmitter systems that have been
found to be involved in placebo and nocebo effects in pain as well as
the growing field of oxytocin and vasopressin in placebo effects,
which may also act as neurotransmitters. Contrary to previous
systematic reviews,58,65 no limitations were applied as to the
methods used to study these neurotransmitter systems.
2. Methods
The methodology and reporting of the study followed the
recommendations and guidelines of the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA).45 The review
was registered with PROSPERO International prospective register of
systematic reviews on July 25, 2017: http://www.crd.york.ac.uk/
PROSPERO/display_record.php?ID5CRD42017071407, with
amendments made on December 13, 2018, and May 23, 2019.
2.1. Search strategy
Placebo studies were identified by searching the electronic
databases PubMed, Embase, Scopus, and the Cochrane
Controlled Register of Trials (the Cochrane Library) using the
search terms: [placebo effect] OR [placebo analgesia] AND [pain]
AND [opioid OR naloxone OR cannabinoid OR dopamine OR
oxytocin OR vasopressin OR cholecystokinin OR CCK]. Nocebo
studies were identified post hoc to be able to investigate
neurotransmitter systems in both placebo and nocebo effects.
The same electronic databases were searched using the search
terms: [nocebo effect] OR [nocebo hyperalgesia] AND [pain] AND
[opioid OR naloxone OR cannabinoid OR dopamine OR oxytocin
OR vasopressin OR cholecystokinin OR CCK]. The search terms
[placebo effect] and [nocebo effect] were also searched as MeSH
(Medical Subject Heading) terms in PubMed and the Cochrane
Library, and as Emtree (Embase Subject Heading) terms in the
Embase database. In the Cochrane Library and the Embase and
Scopus databases, the search terms were marked with an
asterisk (*) to include all possible endings. The searches were
Copyright © 2019 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
PAIN®
limited to English-language articles. The searches were con-
ducted for the period from the earliest dates available in the
databases through May 23, 2019.
2.2. Study selection
2.2.1. Inclusion criteria
(1) The study should be a placebo/nocebo mechanism study in
relation to pain, that is, the aim of the study should be to study
placebo/nocebo mechanisms.
(2) The study should calculate the placebo/nocebo effect as the
difference in pain levels between a placebo/nocebo-treated
group or condition and a no-treated group or condition
(ie, between a pain only and a pain plus placebo/nocebo
condition or between placebo/nocebo conditions with varying
verbal suggestions, or between open and hidden administra-
tion of an active treatment controlled for no treatment).
(3) The study should establish a statistically significant placebo/
nocebo effect.
(4) The study should investigate the neurotransmitter systems
involved in placebo/nocebo effects in pain in healthy
participants or patients with chronic pain; specifically, the
endogenous opioid, endocannabinoid, dopaminergic, oxy-
tocinergic, vasopressinergic, and CCKergic systems.
2.2.2. Exclusion criteria
(5) Reanalyses of data already included in the review.
2.3. Study selection and eligibility
Eligibility assessment of studies and extraction of data were
performed independently by 2 authors (I.S. and S.J.L.), and
disagreements were resolved through discussion with a third
author (L.V.). A fourth author (C.B.) took part in the assessment of
the genetic studies.
2.4. Quality assessment
The methodological quality of the included studies was assessed
by 2 of the authors (I.S. and S.J.L.), who independently read and
assessed the quality of each study. Generally, a high method-
ological quality of the included studies was ensured by the strict
selection criteria. The risk of bias in individual studies was
assessed independently by 2 authors (I.S. and S.J.L.) according
to the Jadad criteria,33 in which studies are coded according to
randomization, blinding, and description of withdrawal and
dropout. The scores range from 0 to 5, where higher scores
indicate a higher methodological quality. Because the aim of
Jadad is to assess the quality of randomized clinical trials (RCTs),
the Jadad scoring was only performed in pharmacological
studies in which an RCT design was used (n 5 20). The risk of
bias across studies was evaluated by comparing the number of
studies with positive vs negative findings.
2.5. Synthesis of results
Due to the heterogeneity of the included studies with respect to
the study design (eg, the method of investigation and outcome
measures), the prevalence or incidence rates could not be simply
combined for meta-analysis.28,65 Instead, we used vote counting,
in which the number of positive studies is counted and compared
with the number of negative studies.28 Specifically, studies were
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assessed according to whether or not they found statistically
significant evidence supporting the involvement of these neuro-
transmitter systems: the endogenous opioid, endocannabinoid,
dopaminergic, oxytocinergic, vasopressinergic, and CCKergic
systems in placebo and nocebo effects in healthy participants
and patients with chronic pain. The balance of positive vs
negative studies was used to determine the answer to the review
questions.
3. Results
A total of 1133 placebo and 147 nocebo articles were identified
through the initial search. Five hundred five placebo and 74
nocebo articles remained for consideration after removal of
duplicates. Of the potential articles screened, 452 placebo and
69 nocebo articles were excluded on the basis of the title and
abstract. The remaining 53 placebo and 5 nocebo articles were
examined in detail (full text). Of these articles, 28 placebo and 2
nocebo articles fulfilled the selection criteria and were included in
the final review. The selection process is illustrated in Figures 1
and 2. The reasons for exclusion of the full-text screened articles
are provided in Appendix A (available as supplemental digital
content at http://links.lww.com/PAIN/A864).
Figure 1. Flow diagram: placebo studies.
Copyright © 2019 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
www.painjournalonline.com 13
3.1. Characteristics of included studies
Characteristics of the 30 included articles are presented in
Table 1. One article used 2 different radiotracers to investigate
the endogenous opioid system and the dopaminergic system in
placebo effects60; thus, the included articles add up to 31
studies. The total number of participants included in the studies
was 2284 including 150 patients with chronic pain and 2134
healthy participants. In the special cases of the included studies
by Peciña et al.47 (n 5 42) and Scott et al.60 (n 5 20), the
participants were a subset of the participants in another
included study conducted by Peciña et al.46 (n 5 50) (e-mail
correspondence with Dr. Marta Peciña on 13 and 14 September
2017). To avoid overrepresentation, the participants were only
counted once in this systematic review, that is, only the 50
participants included in the study by Peciña et al.46 were
included in the calculation of the total number of participants
(Table 1). Yet, the results by Peciña et al’s.46,47 and Scott
et al.60 all contribute to the overall synthesis of results. The
methods used to investigate the neurotransmitter systems
included: pharmacological antagonism or agonism (17), phar-
macological antagonism combined with brain imaging (3), brain
imaging (5), and genetic analyses (5) (Fig. 3).
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I. Skyt et al. 161 (2020) 11–23
Figure 2. Flow diagram: nocebo studies.
3.2. Pain outcome measures
The placebo/nocebo effect was calculated as the difference in pain
levels between a placebo/nocebo-treated group or condition and
a no-treated group or condition (ie, between a pain only and a pain
plus placebo/nocebo condition or between placebo/nocebo
conditions with varying verbal suggestions, or between open and
hidden administration of an active treatment controlled for no
treatment) (cf. selection criterion 2). The primary pain outcome
measure was used to summarize the findings from the included
studies. When no distinction was made between several pain
outcome measures, the pain outcome measure first described was
chosen as the primary outcome.39,46,47,60,62,63,68,71 Seventeen
studies measured pain using a visual analogue scale and 7 studies
used a numerical rating scale.55 Four studies evaluated pain as the
time period (min) that the participants could tolerate an experi-
mental pain stimulus and 1 study used the McGill Pain
Questionnaire.44 Finally, 1 study used the irritable bowel syndrome
(IBS) symptom severity scale that consists of 5 scales with an equal
contribution to the final score: abdominal pain severity, abdominal
pain frequency, abdominal distension severity, dissatisfaction with
bowel habits, and quality-of-life disruption.27
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PAIN®
3.3. Quality assessment
The mean Jadad score was 2.9. Fifteen studies were subtracted
1 point because they did not describe the randomizing procedure
(eg, computer-generated). This is not surprising, given that RCTs
are more strict with respect to predefined criteria for reporting
randomizing procedures. Yet, the studies were published in high-
impact journals, including Nature, Science, and PAIN, with an
impact factor ranging from 3.2 to 47.7 across all journals
represented in this count; so, there is no reason to believe that
the randomization procedure had not been correctly performed,
although it was not described in detail. Hence, the methodolog-
ical quality of the included studies is high. As illustrated in
Figure 4, the review included studies with both positive (24) and
negative (7) findings, which points to a minimized risk of
publication bias.
Taken together, the overall risk of bias of the studies included in
the systematic review is considered acceptable, providing good
strength of evidence for the review conclusions. There were also
no disagreements in the extracting of data across the authors
who independently performed the data extraction (I.S.
and S.J.L.).
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January 2020
Table 1
Characteristics of the included studies.
Article N N in placebo/nocebo Population Pain Primary outcome Design (placebo/ Neurotransmitter Method Design
group(s) measure nocebo effects) system tested (neurotransmitter (pharmacological

·
systems) antagonism/agonism)

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Placebo Studies
Amanzio and 229 Verbal suggestions: 16 Healthy participants Tourniquet Pain tolerance (min) Double-blind, Endogenous opioid Pharmacological Double-blind,
Benedetti1 Verbal suggestions and ischemic pain randomized, between system antagonism (naloxone randomized, between
opioid conditioning: 13 subjects 0.14 mg/kg) subjects

·
Number 1
Opioid conditioning: 14
Verbal suggestions and
nonopioid conditioning: 17
Nonopioid conditioning: 14
Amanzio et al.2,* 86 Open condition: 15 Healthy participants Tourniquet Pain tolerance (min) Double-blind, Endogenous opioid Pharmacological Double-blind,
Hidden condition: 15 ischemic pain randomized, between system antagonism (naloxone randomized, between
subjects 0.14 mg/kg) subjects
Aslaksen et al.3 288 142 Healthy participants Thermal heat pain Pain intensity (VAS) Double-blind, Endogenous opioid Genetic analyses (OPRM1
randomized, between system A118G SNP and COMT
subjects val158met SNP)
Benedetti, et al.6,* 127 15 Healthy participants Tourniquet Pain intensity (0-10 NRS) Double-blind, Endogenous opioid Pharmacological Double-blind,
ischemic pain randomized, between system antagonism randomized, between
subjects (naloxone 10 mg) subjects
Benedetti et al.12 82 Opioid conditioning: 14 Healthy participants Tourniquet Pain tolerance (min) No information on Endocannabinoid system Pharmacological Double-blind,
Nonopioid conditioning: 15 ischemic pain blinding, randomized, antagonism (rimonabant randomized, between
between subjects 0.6 mg kg21) subjects
Benedetti et al.14 173 Verbal suggestion directed Healthy participants Capsaicin burning Time course (AUC 0-15 Double-blind, Endogenous opioid Pharmacological Double-blind,
at left hand: 25 pain min) of pain intensity (0- randomized, between system antagonism (naloxone randomized, between
Verbal suggestions directed 10 NRS) subjects 0.14 mg/kg) subjects
at right hand and left foot:
24
Bingel et al.16 18 18 Healthy participants Laser pain Pain intensity (0-4 NRS) Single-blind, randomized, Endogenous opioid Brain imaging (fMRI)
within subjects system
Colloca et al.20 108 108 Healthy participants Electrical shock Pain intensity (VAS) Single-blind, within Vasopressinergic system Pharmacological Double-blind,
pain subjects agonism (vasopressin: 40 randomized, between
IU) subjects
Colloca et al.21 160 160 Healthy participants Electrical and heat Pain intensity (VAS) Single-blind, within Endogenous opioid Genetic analyses (OPRM1

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pain† subjects system A118G SNP, COMT
val158met SNP and
FAAH Pro129Thr SNP)
Eippert et al.25 40 No information Healthy male Thermal heat pain Pain intensity (VAS) Single-blind, randomized, Endogenous opioid Pharmacological Double-blind,
participants within subjects system antagonism (naloxone randomized, between
0.15 mg/kg 1 subjects
0.2 mg/kr/hr) 1 brain
imaging (fMRI)
Gracely et al.29 89 No information Healthy participants Postoperative McGill pain questionnaire Double-blind, between Endogenous opioid Pharmacological Double-blind, between
dental pain subjects system antagonism (naloxone subjects
10 mg)
(continued on next page)

15
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Table 1 (continued)

16
Article N N in placebo/nocebo Population Pain Primary outcome Design (placebo/ Neurotransmitter Method Design
group(s) measure nocebo effects) system tested (neurotransmitter (pharmacological

I. Skyt et al. 161 (2020) 11–23

systems) antagonism/agonism)
Grevert et al.30 30 16 Healthy participants Tourniquet Pain (VAS) Single-blind, randomized, Endogenous opioid Pharmacological Double-blind,
ischemic pain within subjects system antagonism (naloxone randomized, between
10 mg) subjects

·
Hall et al.31 104 Placebo acupuncture Patients with irritable IBS symptoms IBS symptom severity Double-blind, Dopaminergic system Genetic analyses (COMT
(“limited”): 33 bowel syndrome (IBS) scale randomized, between val158met SNP)
Placebo acupuncture subjects
(“augmented”): 41
Kessner et al.37 75 38 Healthy male Heat pain Pain intensity (VAS) Single-blind, randomized, Oxytocinergic system Pharmacological Double-blind,
participants within subjects agonism (oxytocin 40 IU) randomized, between
subjects
Kupers et al.39 1 1 Woman with low back Low back pain Pain intensity (0-10 NRS) Single-blind (no Endogenous opioid Pharmacological Double-blind, within
pain information on system antagonism (naloxone: subject
practitioner blinding), 0.14 mg/kg) 1 brain
randomized, within imaging (PET)
subject
Levine and 96 12 Healthy participants Postoperative Pain intensity (VAS) Double-blind, Endogenous opioid Pharmacological Double-blind,
Gordon40 dental pain randomized, between system antagonism (naloxone 10 randomized, between
subjects mg) subjects
Peciña et al.46,‡ 50 50 Healthy participants Muscle pain Pain intensity (E-VAS) Single-blind, within Endogenous opioid Genetic analyses (OPRM1
(hypertonic saline subjects system A118G SNP)
5%)
Peciña at al.47,‡ 42§ 42 Healthy participants Muscle pain Pain intensity (E-VAS) Single-blind, within Endocannabinoid system Genetic analyses (FAAH
(hypertonic saline subjects Pro129Thr SNP)
5%)
Petrovic et al.49 9 9 Healthy male Tonic heat pain Pain intensity (VAS) Double-blind, Endogenous opioid Brain imaging (PET;
participants randomized, within system radiotracer: [15O]-H2O)
subjects
Pollo et al.52,* 58 Open/hidden Healthy participants Tourniquet Pain intensity (0-10 NRS) Single-blind, randomized, Endogenous opioid Pharmacological Double-blind, between
condition: 14 ischemic pain within subjects system antagonism (naloxone: subjects
0.14 mg/kg)
Posner et al.53,* 12 12 Healthy participants Tourniquet Pain intensity (VAS) Double-blind, Endogenous opioid Pharmacological Double-blind,
ischemic pain randomized, within system antagonism (naloxone: randomized, within
subjects 0.4 mg/mL) subjects
Scott et al.60 20§ 20 Healthy participants Muscle pain Pain intensity (E-VAS) Single-blind, within Endogenous opioid Brain imaging (PET;
(hypertonic subjects system and the radiotracers: m-opioid
saline 5%) dopaminergic system receptor-selective
agonist [11C] Carfentanil
1 selective dopamine
D2/D3 antagonist [11C]
Raclopride)
Skvortsova et al.62 108 27 Healthy female Cold pressor pain Pain intensity (0-10 NRS) Double-blind,‖ Oxytocinergic system Pharmacological Double-blind,
participants randomized, between agonism (oxytocin: 24 IU) randomized, between
subjects subjects
(continued on next page)

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Table 1 (continued)

January 2020
Article N N in placebo/nocebo Population Pain Primary outcome Design (placebo/ Neurotransmitter Method Design
group(s) measure nocebo effects) system tested (neurotransmitter (pharmacological
systems) antagonism/agonism)
Skyt et al.63 19 Open condition: 19 Neuropathic pain Ongoing Pain intensity (M-VAS) Single-blind, randomized, Dopaminergic system Pharmacological Double-blind,

·
Hidden condition: 19 patients neuropathic pain within subjects antagonism and agonism randomized, within

Volume 161
(haloperidol: 2 mg, subjects
levodopa/carbidopa:
100/25 mg)
Vase et al.68 26 16 Women with irritable Rectal distension Pain intensity (M-VAS) Double-blind, Endogenous opioid Pharmacological Double-blind,

·
bowel syndrome (IBS) counterbalanced,{ within system antagonism (naloxone: randomized, between

Number 1
subjects 10 mg) subjects
Wager et al.69 15 15 Healthy male Thermal pain Stimulus intensity (VAS) Single-blind, randomized, Endogenous opioid Brain imaging (PET;
participants within subjects system radiotracer: m-opioid
receptor-selective
agonist [11C] Carfentanil)
Wrobel et al.70 38 17 Healthy participants Heat pain Pain intensity (VAS) Single-blind, randomized, Dopaminergic system Pharmacological Double-blind,
within subjects antagonism (haloperidol: randomized, between
2 mg) 1 brain imaging subjects
(fMRI)
Zubieta et al.71 14 14 Healthy male Muscle pain Pain intensity (VAS) Single-blind, randomized, Endogenous opioid Brain imaging (PET;
participants (hypertonic within subjects system radiotracer: m-opioid
saline 5%) receptor-selective
agonist [11C] Carfentanil)
Nocebo Studies
Benedetti et al.10,* 180 Open condition: 18 Healthy participants Postoperative Pain intensity (0-10 NRS) Single-blind, randomized, CCKergic system Pharmacological Double-blind,
Hidden condition: 18 chest pain between subjects antagonism (prolugmide: randomized, between
0.05 mg/0.5 mg/5 mg) subjects
Benedetti et al.13,* 49 13 Healthy participants Tourniquet Pain intensity (0-10 NRS) Double-blind CCKergic system Pharmacological Double-blind,
ischemic pain randomized, within antagonism (proglumide: randomized, between
subjects 1.5 mg/kg) subjects
* The study included several parts but only the investigation of the neurotransmitter systems in placebo/nocebo effects in pain was included in this systematic review.
† The participants underwent either electrical (n 5 144) or heat (n 5 16) pain. There was no effect of type of pain on the placebo effect.
‡ The study was part of another study (Neuropsychopharmacology 2013; 38: 639-46), in which the main effects of the placebo effects are reported (personal communication with the first author).
§ The 42 and 20 participants included in these studies were a subgroup of the 50 participants included in study by Peciña et al. (2015) (personal communication with the first author).
‖ One of 2 experimenters was aware of the verbal suggestions given for pain relief. The investigator performing the pain test was blinded to the verbal suggestions.
{ To allow the double blind procedure, the study included an active lidocaine condition, a placebo condition, and a no-treatment condition. The patients were always tested in the no-treatment condition first to determine whether they were hyperalgesic. The order of the active lidocaine condition and the placebo

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condition was counterbalanced.
AUC, area under the curve; COMT, catechol-O-methyltransferase; FAAH, fatty acid amide hydrolase; fMRI, functional magnetic resonance imaging; NRS, numerical rating scale; PET, positron emission tomography; SNP, single-nucleotide polymorphism; VAS, visual analogue scale.

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I. Skyt et al. 161 (2020) 11–23
Figure 3. Method used to investigate neurotransmitter systems in placebo and
nocebo effects.
3.4. Synthesis of results
As illustrated in Figure 4, the number of studies investigating the
neurotransmitter systems in placebo and nocebo effects in
patients with chronic pain is low compared with studies involving
healthy participants.
3.4.1. Placebo effects in healthy participants
3.4.1.1. The endogenous opioid system
Sixteen studies showed that the endogenous opioid system is
involved in placebo effects in healthy participants. Specifically,
8 pharmacological studies (1 also involving brain imaging25)
found that placebo effects can be fully or partially blocked by
administration of the opioid antagonist nalox-
one.1,2,6,14,25,30,40,52 Five brain imaging studies observed
increased opioid and neural activity in opioid-rich descending
pain modulatory structures such as the rostral anterior
cingulate cortex, amygdala, and the periaqueductal gray
during placebo interventions.16,49,60,69,71 Three genetic stud-
ies found an association between the placebo effect and the
A118G single-nucleotide polymorphism (SNP) in the m-opioid
receptor (OPRM1) gene.3,21,46 Two of the studies also found
an interaction effect between the A118G SNP in the m-opioid
receptor gene together with the catechol-O-methyltransferase
(COMT) val158met SNP that influences opioid metabolizing,
but without a main effect of the COMT val158met SNP
alone.3,21 In addition, one of these studies found an interaction
effect between the A118G SNP in the m-opioid receptor gene
together with the Pro129Thr SNP in the fatty acid amide
hydrolase (FAAH) gene, but without a main effect of the FAAH
gene, and, moreover, found a three-way interaction between
the A118G SNP m-opioid receptor gene, the COMT val158met
SNP, and the Pro129Thr SNP in the FAAH gene.21 Together
these findings suggest that the presence and magnitude of
placebo effects are associated with activity of the endogenous
opioid system.
Contrary to this, 2 pharmacological studies found that the
administration of naloxone did not block the placebo effect in
healthy participants.29,53
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PAIN®
3.4.1.2. The endocannabinoid system
Two studies showed that the endocannabinoid system contrib-
utes to placebo effects in healthy participants. A pharmacological
study found that the placebo effect can be blocked by
administration of the CB1 cannabinoid receptor antagonist
rimonabant.12 A genetic study associated the placebo effect
with the Pro129Thr SNP in the FAAH gene, the major degrading
enzyme of endocannabinoids.47
3.4.1.3. The dopaminergic system
Two studies demonstrated mixed results regarding the in-
volvement of the dopaminergic system in placebo effects in
healthy participants. A brain imaging study observed in-
creased dopamine activity in striatal regions (the nucleus
accumbens, ventral putamen, and right ventral caudate
nucleus) during a placebo intervention, 60 pointing to a role of
the dopaminergic system. By contrast, the placebo effects
were not blocked by administration of the dopamine antago-
nist haloperidol at either the behavioral (ie, pain intensity rating)
or neural level (ie, pain-sensitive or pain-modulatory areas) in
a pharmacological study.70
3.4.1.4. The oxytocinergic system
Two studies demonstrated mixed results regarding the in-
volvement of the oxytocinergic system in placebo effects in
healthy participants. One pharmacological study found that
administration of oxytocin (oxytocin agonist) enhanced the
placebo effect and pointed to the involvement of the oxy-
tocinergic system.37 Another pharmacological study found that
the placebo effect was not enhanced by the administration of
oxytocin.62
3.4.1.5. The vasopressinergic system
One pharmacological study found that the administration of
a vasopressin agonist can enhance the placebo effect in healthy
participants and pointed to the involvement of the vasopressi-
nergic system.20
3.4.1.6. The CCKergic system
There are no studies of involvement of the CCKergic system in
placebo effects in healthy participants.
3.4.2. Placebo effects in patients with chronic pain
3.4.2.1. The endogenous opioid system
Two studies found that administration of naloxone did not block
placebo effects in patients with chronic pain, suggesting that the
endogenous opioid system is not involved in placebo effects in
chronic pain.39,68
3.4.2.2. The endocannabinoid system
There are no studies of involvement of the endocannabinoid
system in placebo effects in patients with chronic pain.
3.4.2.3. The dopaminergic system
Two studies demonstrated mixed results regarding the involve-
ment of the dopaminergic system in placebo effects in patients
with chronic pain. A genetic study found an association in
patients with IBS between the placebo effect and the val158met
SNP in the COMT gene, an enzyme that breaks down dopamine
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· Number 1 www.painjournalonline.com 19

Figure 4. Synthesis of findings from the included studies (vote counting). *There are no studies of involvement of the cholecystokinergic system in placebo effects,
and there are no studies of involvement of endogenous opioid, endocannabinoid, dopaminergic, oxytocinergic, and vasopressinergic systems in nocebo effects.

including in the prefrontal cortex.31 Specifically, the magnitude of
the placebo effect increased progressively with the progressive
increase in the number of COMT val158met alleles from 0 to 1 to
2, which resulted in significantly decreased COMT enzyme
activity and thus theoretically more available dopamine in the
prefrontal cortex. The study included a no-treated control arm
and 2 placebo acupuncture arms: a “limited” placebo acupunc-
ture group, involving a business-like patient–practitioner in-
teraction, and an “augmented” placebo acupuncture group, in
which the placebo acupuncture was given in a supportive
patient–provider interaction. The placebo effect was larger in
the augmented than in the limited treatment arm, but the COMT
val158met SNP only predicted the treatment response in the
augmented treatment group.31 Contrary to this, a pharmacolog-
ical study found that administration of neither the dopamine
antagonist haloperidol nor the dopamine agonist levodopa/
carbidopa affected the placebo effect in patients with neuro-
pathic pain.63
3.4.2.6. The CCKergic system
There are no studies of involvement of the CCKergic system in
placebo effects in patients with chronic pain.
3.4.3. Nocebo effects in healthy participants
3.4.3.1. The endogenous opioid, endocannabinoid,
dopaminergic, oxytocinergic, and vasopressinergic systems
There are no studies of involvement of the endogenous opioid,
endocannabinoid, dopaminergic oxytocinergic, and vasopressi-
nergic systems in nocebo effects in healthy participants.
3.4.3.2. The CCKergic system
Two studies showed that nocebo effects were blocked by the
CCK antagonist proglumide, suggesting that the CCKergic
system is involved in nocebo effects in healthy participants.10,13

3.4.2.4. The oxytocinergic system
There are no studies of the involvement of the oxytocinergic
system in placebo effects in patients with chronic pain.
3.4.2.5. The vasopressinergic system
There are no studies of the involvement of the vasopressinergic
system in placebo effects in patients with chronic pain.
3.4.4. Nocebo effects in patients with chronic pain
3.4.4.1. The endogenous opioid, endocannabinoid,
dopaminergic, oxytocinergic, and vasopressinergic systems
There are no studies of involvement of the endogenous opioid,
endocannabinoid, dopaminergic oxytocinergic, and vasopressi-
nergic systems in nocebo effects in patients with chronic pain.

Copyright © 2019 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
 20
·
I. Skyt et al. 161 (2020) 11–23
3.4.4.2. The CCKergic system
There are no studies of involvement of the CCKergic system in
nocebo effects in patients with chronic pain.
4. Discussion
The involvement of the endogenous opioid system in placebo effects
in healthy participants has been extensively investigated, and there
are clear positive indications that the release of endogenous opioids
contributes to placebo effects in healthy participants. A few studies
point to the involvement of the endocannabinoid and vaso-
pressinergic systems, whereas the findings regarding the dopami-
nergic and oxytocinergic systems are mixed. The number of studies
of the neurotransmitter systems in placebo effects in chronic pain is
limited. These studies show no involvement of the endogenous
opioid system and mixed findings regarding the dopaminergic
system. As to the neurotransmitter systems involved in nocebo
effects, 2 studies point to the involvement of the CCKergic system in
nocebo effects in healthy participants, whereas this has not been
investigated in patients with chronic pain.
4.1. Neurotransmitter involvement in placebo effects in
healthy participants
Our knowledge of the endogenous opioid system in placebo
effects in healthy participants is based on a large number of
studies applying different but complementary methods. The
findings clearly indicate that the release of endogenous opioids
contributes to placebo effects in healthy participants25,40,69
which is consistent with the results of previous systematic
reviews.58,65 A recent meta-analysis demonstrated that placebo
treatments only have a small effect on early nociceptive
processing,72 suggesting a prominent role of higher cognitive
pain modulation. This systematic review shows that opioid-rich
descending pain modulatory structures such as the rostral
anterior cingulate cortex, amygdala, and periaqueductal gray
play a key role in placebo effects.16,17,25,66,71
Compared with the well-studied endogenous opioid system,
the endocannabinoid, dopaminergic, oxytocinergic, and vaso-
pressinergic systems have been investigated only to a lesser
extent. This systematic review inclines to the involvement of the
endocannabinoid12,47 and vasopressinergic20 systems in pla-
cebo effects, whereas the findings regarding the dopaminer-
gic60,70 and oxytocinergic37,62 systems are mixed. Other studies
not included in this systematic review due to a lack of a statistically
significant placebo effect also found no involvement of the
dopaminergic system in placebo effects in healthy partici-
pants.34,73 Furthermore, a study by Colloca et al.20 found no
involvement of oxytocin; however, the data were evaluated only in
relation to the vasopressinergic system in the present review
because data on oxytocin were not specified in the result section
of this study. Based on these mixed results, it seems preliminary
to evaluate the role of the dopaminergic and oxytocinergic
systems in placebo effects. As regards the oxytocinergic system,
the mixed findings have been related to oxytocin dosage and
participants’ sex,62 which may be important considerations in
future studies. Specifically, the administration of 40 IU of oxytocin
has been found to enhance placebo effects,37 whereas 24 IU of
oxytocin does not enhance placebo effects.20,62 In addition,
oxytocin has been shown to enhance placebo effects in healthy
men37 but not in healthy women62 or in studies conducted in both
men and women.20 By contrast, the administration of vaso-
pressin enhances placebo effects in women.20 Oxytocin and
vasopressin are both known modulators of social behaviors, but
Copyright © 2019 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
PAIN®
the specific influence of these neurotransmitters is sex de-
pendent.26,57 Because placebo effects are strongly associated
with social interactions such as the patient–practitioner relation-
ship,36 there may be sex differences in the way that oxytocin and
vasopressin influence placebo effects. Regarding the dopami-
nergic system, a noteworthy consideration relates to the
hypothesis that dopamine is involved in the anticipation of
a treatment effect rather than to the actual symptom relief after
a placebo intervention.22 Exemplifying this, a brain imaging study
has observed increased dopamine activity during the introduction
and anticipation of a placebo treatment but not during the
introduction of pain and placebo.59 The present review only
investigated placebo effects in relation to actual pain levels and
not during anticipation of placebo, but it may be beneficial in
future studies to continue to explore whether expectations of
analgesia are associated with dopamine release.
4.2. Neurotransmitter involvement in placebo effects in
patients with chronic pain
As illustrated in Figure 4, there are only few studies of the
neurotransmitter systems involved in placebo effects in chronic
pain. Contrary to the well-established role of the endogenous
opioid system in placebo effects in healthy participants,25,40,69
the preliminary findings suggest that placebo effects in chronic
pain may not be mediated by endogenous opioids.39,68 Due to
the limited evidence and the low number of patients in these
studies, we cannot rule out the possibility of a type 2 error (false
negative). Accordingly, it will be important that future studies
continue to investigate this. Yet, patients with chronic pain may
have problems activating the endogenous opioid circuitry,61,64
and nonopioid mechanisms have been suggested to mediate this
type of placebo effects.68 Interestingly, studies in healthy
participants show that placebo effects that are induced through
opioid conditioning involve the endogenous opioid system,
whereas placebo effects that are induced through nonopioid
conditioning involve the endocannabinoid system.12 The neuro-
transmitters mediating placebo effects in chronic pain may
depend on the patients’ previous treatment experiences in
a similar way; so, it will be relevant to ask the patients about
their treatment history in future studies. In addition, this study12
points to the endocannabinoid system as one candidate
mechanism possibly underlying nonopioid-mediated placebo
effects in chronic pain, although this is yet to be investigated. A
study investigating the effect of verbal suggestions on pain levels
also points to a possible role of the endocannabinoid system in
placebo effects.15 This study showed that positive verbal
suggestions about an experimental pain stimulus (“this procedure
may be beneficial to muscle cells”) increased pain tolerance,
which, in turn, involved the coactivation of the endogenous opioid
and endocannabinoid systems. Specifically, the tolerance-
increasing effect was partially blocked by antagonism of opioid
or endocannabinoid receptors, whereas the combined antago-
nism completely blocked the effect. Interestingly, there was
a negative correlation between the role of the endogenous opioid
and endocannabinoid systems, suggesting that the involvement
of endocannabinoids increased progressively with decreased
involvement of endogenous opioids.15 However, because these
studies involved healthy participants, it is recommended that
future studies investigate the endocannabinoid system in placebo
effects in patients with chronic pain. Notably, due to adverse
events, there are currently regulations against human use of
rimonabant, and studies may depend on other methods such as
genetic analysis47 and brain imaging.42
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So far, only one study points to neurotransmitter involvement in
placebo effects in chronic pain.31 In this study, genetic analyses
found an association in patients with IBS between the placebo
effect and the COMT val158met SNP that influences dopamine
levels in the prefrontal cortex. The study showed that the
magnitude of the placebo effect increased proportionally with
the number of met alleles, likely resulting in lower COMT enzyme
activity and thus a lower degradation of available dopamine in the
prefrontal cortex. However, the study contains some limitations
with respect to the investigation of neurotransmitters in placebo
effects in pain, and the findings may therefore be interpreted with
caution. First, the COMT val158met SNP only predicted the
treatment response in the augmented treatment group, in which
the treatment was given in a supportive patient–provider in-
teraction; so, the findings may express the benefits that follow
a supportive patient–provider interaction rather than the placebo
intervention per se. Second, the IBS symptom severity scale that
consists of 5 scales with an equal contribution to the final score
was used as the primary outcome measure in this study.27
Because only some of these scales are related to pain, it is
uncertain whether dopamine was related to the pain relief rather
than, for example, quality of life. On the contrary, a pharmaco-
logical study found no effect of antagonism or agonism of
dopamine receptors on the placebo effect in patient with
neuropathic pain,63 suggesting that the dopaminergic system is
not involved in this type of placebo effects. One possible
explanation to this relates to the type of pain under investigation
that may vary with respect to the underlying pathophysiol-
ogy.35,50,67 Because the findings are mixed, more studies are
warranted, not only in relation to the dopaminergic system but
also to the endogenous opioid, endocannabinoid, oxytocinergic,
and vasopressinergic systems, and these studies may advanta-
geously include patients with different types of chronic pain.
4.3. Neurotransmitter involvement in nocebo effects
Only 2 studies have investigated the neurotransmitter systems in
nocebo effects, both involving healthy participants.10,13 Although
these studies point to a role of the CCKergic system, future
studies are needed, and it will be important to also investigate this
in patients with chronic pain.
Interestingly, the CCKergic system has been found to have
antiopioid actions4,9,18 and, in addition to blocking of nocebo
effects,10,13 previous studies have shown that the CCK antag-
onist proglumide potentiates placebo effects.6,11 On this basis, it
can be speculated that the analgesic placebo effect and
hyperalgesic nocebo effect involve opposite activation of the
endogenous opioid system. Yet, in one of the studies included in
this systematic review, the opioid antagonist naloxone did not
prevent the attenuating effect of proglumide on the nocebo
effect.10 Thus, although nocebo effects are often described as
the negative counterpart of the placebo effect18,51 with opposite
effects on pain, these findings suggest that placebo and nocebo
effects do not involve opposite neurotransmission activity, at least
not in the endogenous opioid system.
4.4. Conclusion and future directions
Research has come a long way in specifying the neurotransmitter
systems involved in placebo effects in pain, and there is strong
evidence for the involvement of the endogenous opioid system in
placebo effects in healthy participants. A few studies point to the
involvement of other neurotransmitter systems, but more research
is warranted. Most studies have been conducted in healthy
Copyright © 2019 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
www.painjournalonline.com 21
participants, and it is currently unknown whether the release of
neurotransmitters contributes to placebo effects in chronic pain.
Notably, the preliminary findings suggest that the endogenous
opioid system may not be involved in placebo effects in chronic
pain39,68; so, findings from studies conducted in healthy partic-
ipants may not necessarily apply to chronic pain. Yet, due to the
limited number of studies, more research is needed to make firm
conclusions. Interestingly, however, psychological mechanisms
involved in placebo effects in healthy participants and patients with
chronic pain have also been suggested to differ. Specifically,
a recent meta-analysis showed medium to large effects of
interventions aimed at altering expectations (eg, verbal sugges-
tions) on placebo effects in experimental and acute postoperative
pain but only small effects on placebo effects in chronic pain.48
The neurotransmitter systems involved in nocebo effects have
only been scarcely investigated. Two studies point to the
involvement of the CCKergic system in nocebo effects in healthy
participants, whereas this has not been investigated in patients
with chronic pain.
Neurotransmitter systems have also been found to be involved
in placebo effects related to other diseases than pain. The
dopaminergic system has, for example, been found to be
involved in placebo effects in Parkinson disease.23,24 Future
research should investigate the involvement of neurotransmitter
systems in placebo and nocebo effects in chronic pain as well as
in other clinical conditions outside the field of pain to elaborate our
understanding of the possible shared—or different—
mechanisms underlying placebo and nocebo effects in different
populations and conditions.
Conflict of interest statement
The authors report no conflicts of interest.
Acknowledgements
The authors thank Helle O. Andersen and Annie D. Kristensen for
proofreading the manuscript.
Appendix A. Supplemental digital content
Supplemental digital content associated with this article can be
found online at http://links.lww.com/PAIN/A864.
Supplemental video content
A video abstract associated with this article can be found at http://
links.lww.com/PAIN/A875.
Article history:
Received 15 February 2019
Received in revised form 27 June 2019
Accepted 6 August 2019
Available online 23 August 2019
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