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Systematic Reviews and Meta-Analyses

Neurotransmitter systems involved in placebo and nocebo effects in healthy participants and patients with chronic pain: a systematic review

Skyt, Inaa,*; Lunde, Sigrid J.a; Baastrup, Cathrineb; Svensson, Peterc,d; Jensen, Troels S.e,f; Vase, Lenea

Author Information
doi: 10.1097/j.pain.0000000000001682

Abstract

1. Introduction

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 mechanisms. Most of these studies have been conducted in healthy participants exposed to experimental pain1,6,10,14,25 or experiencing 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 is therefore essential to directly investigate the neurotransmitter 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 oxytocinergic,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 mechanisms 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 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 studies, 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 system.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 µ-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, oxytocinergic, vasopressinergic, and CCKergic systems in placebo and nocebo effects. To the best of our knowledge, this encompasses 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?ID=CRD42017071407, 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 limited to English-language articles. The searches were conducted 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 administration 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, oxytocinergic, 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 methodological 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 = 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 assessed according to whether or not they found statistically significant evidence supporting the involvement of these neurotransmitter 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.
Figure 1.:
Flow diagram: placebo studies.
Figure 2.
Figure 2.:
Flow diagram: nocebo studies.

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 = 42) and Scott et al.60 (n = 20), the participants were a subset of the participants in another included study conducted by Peciña et al.46 (n = 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), pharmacological antagonism combined with brain imaging (3), brain imaging (5), and genetic analyses (5) (Fig. 3).

Table 1
Table 1:
Characteristics of the included studies.
Table 1-a
Table 1-a:
Characteristics of the included studies.
Table 1-b
Table 1-b:
Characteristics of the included studies.
Figure 3.
Figure 3.:
Method used to investigate neurotransmitter systems in placebo and nocebo effects.

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 experimental 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

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 methodological 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.

Figure 4.
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.

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.).

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 naloxone.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 studies found an association between the placebo effect and the A118G single-nucleotide polymorphism (SNP) in the µ-opioid receptor (OPRM1) gene.3,21,46 Two of the studies also found an interaction effect between the A118G SNP in the µ-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 µ-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 µ-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

3.4.1.2. The endocannabinoid system

Two studies showed that the endocannabinoid system contributes 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 involvement of the dopaminergic system in placebo effects in healthy participants. A brain imaging study observed increased 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 antagonist 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 involvement 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 oxytocinergic 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 vasopressinergic 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 involvement 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 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 acupuncture group, involving a business-like patient–practitioner interaction, 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 pharmacological study found that administration of neither the dopamine antagonist haloperidol nor the dopamine agonist levodopa/carbidopa affected the placebo effect in patients with neuropathic pain.63

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.

3.4.2.6. 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 vasopressinergic 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

3.4.4. 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 vasopressinergic systems in nocebo effects in patients with chronic pain.

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 vasopressinergic systems, whereas the findings regarding the dopaminergic 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 vasopressinergic systems have been investigated only to a lesser extent. This systematic review inclines to the involvement of the endocannabinoid12,47 and vasopressinergic20 systems in placebo effects, whereas the findings regarding the dopaminergic60,70 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 participants.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 vasopressin enhances placebo effects in women.20 Oxytocin and vasopressin are both known modulators of social behaviors, but the specific influence of these neurotransmitters is sex dependent.26,57 Because placebo effects are strongly associated with social interactions such as the patient–practitioner relationship,36 there may be sex differences in the way that oxytocin and vasopressin influence placebo effects. Regarding the dopaminergic 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 neurotransmitters 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 antagonism 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

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 interaction; 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 pharmacological 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 pathophysiology.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 advantageously 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 antagonist 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 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 participants 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 suggestions) 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.

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.

Acknowledgements

The authors thank Helle O. Andersen and Annie D. Kristensen for proofreading the manuscript.

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Keywords:

Placebo and nocebo effects; Pain; Neurotransmitter systems; Healthy participants; Patients with chronic pain

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