Journal Logo

ORIGINAL ARTICLES

Antipruritic Placebo Effects by Conditioning H1-antihistamine

Meeuwis, Stefanie H. MSc; van Middendorp, Henriët PhD; Pacheco-Lopez, Gustavo PhD; Ninaber, Maarten K. MD, PhD; Lavrijsen, Adriana P.M. MD, PhD; van der Wee, Nic MD, PhD; Veldhuijzen, Dieuwke S. PhD; Evers, Andrea W.M. PhD

Author Information
doi: 10.1097/PSY.0000000000000743

Abstract

INTRODUCTION

Placebo effects are beneficial effects that cannot be attributed to active treatment ingredients (1,2). Instead, these effects are ascribed to expectancy mechanisms, with expectations of benefit resulting in improvement of somatic symptoms (e.g., itch and pain (3–6)). The opposite has also been demonstrated, with expectations of deterioration resulting in exacerbation of symptoms or increased adverse effects (i.e., nocebo effects (3,7)). Current evidence shows that placebo and nocebo effects can be induced through multiple pathways, for example, by providing positive or negative information regarding treatments, or through associative learning processes such as conditioning (8–10). In behavioral conditioning, repeated pairing of an initially neutral stimulus (to-be conditioned stimulus [CS]) with an unconditioned stimulus (UCS), which elicits a certain innate response, may lead to the CS eliciting a similar response (conditioned response), even when the UCS is not presented (9,10).

There is evidence that conditioning of allergens to a CS can exacerbate allergic symptoms, upregulate histamine release in animal models of allergy (which has been linked to exacerbation of allergic responses), and adversely influence itch (11–20). Moreover, studies indicate that conditioning can also potentially alleviate allergic symptoms by repeatedly pairing a CS (e.g., a novel-tasting beverage) with an H1-antihistamine (e.g., desloratadine) as UCS (21,22). This has previously resulted in a conditioned basophil response to dust mite allergens (21). However, findings for subjective symptoms were less clear, as these also tended to decrease in the control groups (21,22). Moreover, no study to date has investigated whether conditioning of H1-antihistamine may influence histamine-induced itch specifically. Because histamine is a modulator of itch not only in allergic conditions but also in other inflammatory conditions such as atopic dermatitis (23,24), demonstrating these effects may provide a basis for new therapeutic approaches aimed at enhancement of placebo responses, reduction of medication use, and minimization of adverse effects (25,26).

Traditionally, a blinded study protocol is used for behavioral conditioning, in which participants do not know whether they receive medication or inert pills (27). This makes direct translation of these effects to clinical practice difficult, as it insinuates that deception is needed to elicit placebo effects, and patients in clinical practice need to be fully informed about treatment (27). However, there is accumulating evidence that placebo effects may also occur when it is known that an inert substance is given (i.e., open-label). Symptoms of allergic rhinitis, irritable bowel syndrome, and chronic low back pain can be reduced when placebo pills are given together with a rationale explaining the placebo effect (28–34). The efficacy of open-label conditioning (i.e., explaining the learning procedure from the beginning) for reduction of symptoms such as itch has not yet been demonstrated.

The current study investigated whether behavioral conditioning of the antihistaminergic properties of levocetirizine could reduce itch in response to a short-term histamine challenge. Effects of behavioral conditioning on other clinical, physiological, and psychological responses were explored. Moreover, the study aimed to explore the effects of open- versus closed-label conditioning.

MATERIALS AND METHODS

Study Design

Detailed methodology is described in the Methods section in the Supplemental Material, Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581. This study was a block-randomized (1:1:1:1), placebo-controlled crossover study (Dutch Trial Registry ID: NTR5544, registration on October 6, 2015) that was approved by the Medical Ethical Committee at the Leiden University Medical Center, the Netherlands (ID NL52687.058.15) and conducted in concordance with the Declaration of Helsinki (35). All participants provided written informed consent. Data for the study were collected between October 2015 and October 2017.

Conditioning Paradigm and Blinding

In line with previous studies (21,22,36–39), a two-phase conditioning paradigm was applied that consisted of an acquisition phase, in which a distinctively tasting beverage (to-be CS) was combined with a UCS (a capsule containing 5 mg levocetirizine diHCl, an H1-antihistamine) or an identically looking placebo capsule, and an evocation phase, in which the CS was combined with a placebo capsule. Both phases had three sessions on three consecutive days, and were separated by a 4-day drug washout period. Participants were allocated to I) an open-label conditioned group (acquisition: CS + UCS with an explanation of conditioning and its expected effects; evocation: CS + placebo); II) a closed-label conditioned group (acquisition: CS + UCS; evocation: CS + placebo); III) a conditioned-not-evoked control group (acquisition: CS + UCS; evocation: water + placebo), which was added to control for carry-over effects of the conditioning procedure; or IV) a nonconditioned control group (acquisition: CS + placebo; evocation: CS + placebo), which was added to control for the effects of CS only. Block randomization was used to generate a randomization sequence and was managed by an independent party (the Leiden University Medical Center pharmacy that distributed the UCS and placebo capsules). The study was conducted double blinded for the closed-label conditioned group and nonconditioned control group, single blinded for the conditioned-not-evoked group, and nonblinded for the open-label conditioned group. In the conditioned-not-evoked group, the CS was not administered during evocation, and the acquisition phase was conducted by a different experimenter in a different laboratory setting (e.g., location and lighting), to prevent conditioning to the environment. In the open-label conditioned group, the experimenter provided participants with information regarding the conditioning procedure at the start of acquisition (see the Supplemental Material for further details, Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581). Notification of allocation to these two groups by the pharmacy was given to the experimenter after inclusion.

Participants

Healthy male and female volunteers aged between 18 and 35 years were recruited for this study. Inclusion criteria consisted of a good understanding of written and spoken Dutch, and absence of allergic rhinitis or allergic conjunctivitis within 3 months before enrollment in the study. Potential participants were excluded in case of somatic or psychological morbidities that may interfere with the study protocol or participants’ safety; allergic rhinitis or conjunctivitis within 3 months before participation; any allergic condition presenting symptoms other than rhinitis or conjunctivitis; recent use of analgesics, antibiotics, antihistamines, or anti-inflammatory medication; recent vaccinations; (intended) pregnancy; or intolerance for any substances used in the study.

Procedure and Study Outcomes

An overview of the study protocol is provided in Figure 1. The study took place at Leiden University and was advertised as a study on the influence of psychological factors on antiallergic medication. Participants were invited for a screening session, and upon inclusion, psychological factors and expected itch were assessed. Well-being was measured through questionnaires (measurement set A; i.e., Positive and Negative Affect Schedule (40)), State Trait Anxiety Index–State Anxiety (41)), and Numeric Rating Scales (NRS) for general well-being items). Next, spirometry (forced vital capacity [FVC%predicted], forced expiratory volume in 1 second [FEV1%predicted]) was assessed, and 5-minute measures of heart rate (HR) and skin conductance level (SCL) were taken (measurement set B). Itch was induced experimentally through 2.5 minutes of transdermal iontophoresis with a 0.6% diphosphate histamine solution on the volar side of the nondominant forearm. Itch was assessed verbally every 30 seconds during iontophoresis, and the self-rated and clinical skin response to histamine was measured (measurement set C). Finally, participants indicated how much itch they expected to experience during the final evocation session, and blood samples were taken to assess eosinophil profile and immunoglobulin E response to aeroallergens. In the next week, participants were invited for the acquisition sessions. For each of the three acquisition sessions, measurement set A was assessed before the CS was administered with the UCS or placebo pill. After a 4-day drug washout, participants were invited for the evocation sessions. During evocation, measurement sets A + B were assessed pre-CS, and +30 and +60 minutes post-CS administration, with an additional +90-minute post-CS assessment for the final session. Measurement set C (histamine iontophoresis) was reassessed in the final session between +60 and +90 minutes post-CS. At the start of the final session, expected itch, remembered itch, and expected medication efficacy were assessed. Finally, participants filled in a closing questionnaire in which they indicated whether they suspected to have received placebo or active medication, and compared the itch experienced during both tests. Participants rated the pleasantness of the CS taste in each session on an NRS. Participation was reimbursed by €150. An overview of the measurement schedule is provided in Figure 2.

FIGURE 1
FIGURE 1:
Overview of the study protocol. A conditioned stimulus (CS; distinctively tasting drink) was combined with an unconditioned stimulus (UCS; levocetrizine) or placebo capsule (PLAC) during acquisition. During evocation, the CS was combined with PLAC, and for the conditioned-not-evoked group, PLAC was provided with water (H2O). Histamine iontophoresis (ITCH) was conducted at baseline and in the final evocation session.
FIGURE 2
FIGURE 2:
Overview of the measurement schedule. Numbers on the timeline are deducted from CS administration, with −10 representing pre-CS, and +30, +60, and +90 representing post-CS measurements. Personality questionnaires (Q); expected itch (EXP); measurement sets for well-being (A); spirometry, heart rate, and skin conductance (B); and histamine iontophoresis (e.g., itch; C) and blood samples (BL) were taken. Filler tasks consisted of neutral magazines, Sudokus, and puzzles.

Power Calculation and Statistical Analysis

A detailed description of the statistical analyses can be found in the Methods section in the Supplemental Material, Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581. An a priori power calculation using 1000 simulated data sets at a power level of β = 0.85, an α level of α = .05, and an assumed effect size of Δ/σ = 1/1 indicated that 92 participants were needed to find differences between the four groups. All analyses were performed using SPSS 23.0 for Windows (IBM SPSS Inc., Chicago, Illinois). As described in the a priori plan for the statistical analyses, differences in mean itch during iontophoresis in the evocation phase between the combined open- and closed-label conditioned groups and the combined control groups were assessed using a one-sided general linear model (GLM) analysis of covariance (ANCOVA), including baseline itch as covariate. Secondarily, a GLM ANCOVA was conducted two-sided to explore effects between the separate groups. In case of significant group effects, Bonferroni post hoc tests were conducted. These analyses were repeated for the secondary parameters itch expectation and other iontophoresis-related outcomes (measurement set C). For well-being and physiological outcomes (measurement sets A + B), mixed between-within-subject repeated-measures analysis of variance (RMAs) were conducted. In case of significant effects, within-subject RMAs were conducted post hoc to assess changes from baseline for individual groups. The groups were compared on the closing questionnaire items by χ2 tests. Relations between suspected medication intake and the primary outcome of itch were assessed by GLM ANCOVAs. Because the open-label group received information on medication administration, analyses for the closing questionnaire items were repeated without this group. Assumptions were checked before analyses, and all analyses were conducted with α = .05. As an effect size, η2partial was calculated for each analysis. All values in the Results section represent mean (standard deviation, or M [SD]), unless stated otherwise.

RESULTS

Participants

Ninety-nine participants were included in the study, of whom seven dropped out of the study after inclusion for various reasons. For a complete overview of participants’ flow, see Supplemental Figure 1, Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581. The final sample consisted of 92 participants (Mage [SD], 22.1 [2.5] years; 84% female) randomized to the open-label conditioned group (n = 23), the closed-label conditioned group (n = 24), the conditioned-not-evoked control group (n = 23), or the nonconditioned control group (n = 22). Participants did not differ significantly between groups on demographic factors (see Table 1 [combined groups] and Supplemental Table 1 [separate groups], Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581).

TABLE 1
TABLE 1:
Means, SDs and Analyses of (Co)Variance Results for the Combined Conditioned Groups Versus the Combined Control Groups

Group Differences at Baseline and During the Acquisition Phase

Participants randomized to the combined open- and closed-label conditioned groups showed a larger wheal area after baseline histamine iontophoresis (M [SD], 12.3 [3.1]) compared with the combined control groups (M [SD], 10.6 [3.6]; F(1,88) = 6.14, p = .015, η2partial = 0.07). A marginal overall difference between the separate groups was found for positive affect on the second acquisition day (F(3,88) = 2.61, p = .057, η2partial = 0.08; Bonferroni post hoc tests: p > .31). No other differences were found between groups at baseline, or at the pre-CS measurements during the acquisition and evocation sessions (all, p > .09). Groups did not differ in their rating of the pleasantness of the taste of the CS (all, p > .20), which was generally rated as unpleasant (Mrating [SD], 3.8 [1.5]).

Expected Itch

No differences in expected itch, remembered itch, or expected medication efficacy were found between the combined conditioned groups and the control groups (all, p > .11). When effects of separate groups were explored, a medium-sized effect on expected itch was demonstrated (F(3,86) = 2.96, p = .037, η2partial = 0.09), with post hoc Bonferroni tests illustrating that the open-label conditioned group expected borderline significantly less itch (M [SD], 3.2 [2.2]) compared with the conditioned-not-evoked group (M [SD], 4.6 [1.6]; p = .050; Figure 3 and Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581).

FIGURE 3
FIGURE 3:
Means and standard errors of expected itch, with (A) the effects of the combined conditioned groups and the combined control groups on expected itch, controlled for baseline expected itch as measured postiontophoresis during the screening, and (B) the effects of the separate groups on expected itch.

Mean Self-reported Itch

As illustrated in Figure 4, a marginal small-sized conditioned effect was demonstrated for mean itch (F(1,88) = 2.10, p = .076, η2partial = 0.02), with the combined conditioned groups reporting lower itch compared with the combined control groups in response to iontophoresis during evocation (Mdifference, −0.34; standard error, 0.24). A nonsignificant difference in itch was found when analyses were repeated for the separate groups (F(3,86) = 1.47, p = .23, η2partial = 0.05).

FIGURE 4
FIGURE 4:
Means and standard errors of the mean for itch during iontophoresis in the final evocation session, with (A) mean itch for the combined conditioned and the combined control groups, and (B) mean itch for the separate groups.

Self-rated and Clinical Skin Response to Histamine Iontophoresis

No effects on self-rated skin response to iontophoresis were demonstrated for both the combined (F(1,88) = 0.47, p = .25, η2partial = 0.01) and separate group analyses (F(3,86) = 0.53, p = .66, η2partial = 0.02). Moreover, no effects were detected for the clinical skin response parameters (all, p > .21; see also Table 1 [combined groups] and Supplemental Table 1 [separate groups], Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581).

Spirometry

No significant group by time interactions were found for FVC%predicted or FEV1%predicted during the course of the evocation sessions for both the combined and separate group analyses (all, p > .32), indicating that conditioning did not evoke changes in spirometry over time. In addition, no main effect of group on spirometry parameters was found (all, p > .13; Supplemental Tables 2 and 3, Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581).

HR and SCL

A medium-sized significant group by time interaction was demonstrated in the combined groups for HR (Wilk λ = 0.83, F(7,80) = 2.35, p = .031, η2partial = 0.17). Separate-group RMAs demonstrated an overall reduction in HR compared with baseline for both conditioned and control groups (both, Wilk λ > 0.25; both, p < .001). Post hoc comparisons over time demonstrated that in the combined conditioned groups, HR was significantly reduced compared with baseline for only three of seven post-CS measures (p ≤ .001). In the combined control groups, HR was significantly reduced compared with baseline for six of seven post-CS measures (p ≤ .001) and marginally reduced for the other (1/7) post-CS measure (p = .075). When analyses were repeated for the four (noncombined) groups, a similar medium-sized group by time interaction was found (Wilk λ = 0.64, F(21,225) = 1.79, p = .021, η2partial = 0.14). Post hoc separate-group RMAs and pairwise comparisons demonstrated significant HR reduction in line with the patterns for the combined groups. No group by time interactions (both, p > .44) or main effects of group (both, p > .43) were found for SCL in analyses with combined or separate groups. An overview is provided in Supplemental Tables 2 and 3, Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581.

Well-being

No group by time interactions (all, p > .23) or main effects of group (all, p > .11) were demonstrated for the Positive and Negative Affect Schedule positive affect, State Trait Anxiety Index–State Anxiety, or NRS general well-being measures for both the combined and separate group analyses (see Supplemental Table 2 and 3, Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581).

Closing Questionnaire: Suspected Medication Intake and Its Association With Mean Itch and Other Iontophoresis-Related Outcomes

No differences between groups were found when participants compared baseline and evocation itch in the closing questionnaire (all, p > .15). The groups differed marginally to significantly in suspected medication intake for all sessions (all, p < .066), except for the first evocation session. When the open-label conditioned group was excluded from the analysis, no differences were found (all, p > .11). Participants who suspected taking active medication during the final evocation session had reported less itch during iontophoresis as compared with those who suspected taking placebo (open-label conditioned group included: F(1,88) = 3.82, p = .054, η2partial = 0.04; open-label conditioned group excluded: F(1,65) = 6.09, p = .016, η2partial = 0.09) and also reported lower subjective skin response (open-label conditioned group included: F(1,88) = 5.95, p = .017, η2partial = 0.06; open-label conditioned group excluded: F(1,65) = 4.92, p = .030, η2partial = 0.07; Supplemental Tables 4 and 5, Supplemental Digital Content 1, http://links.lww.com/PSYMED/A581).

DISCUSSION

The current study investigated whether behavioral conditioning of the antihistaminergic properties of levocetirizine could reduce itch and other clinical, physiological, and psychological responses to histamine, under both open-label (i.e., with participants knowing about the conditioning procedure) and closed-label conditions. Conditioning was found to be marginally effective in reducing itch when the combined conditioned groups were compared with the combined control groups. However, no effects of conditioning were found for self-rated or clinical skin responses to histamine. Marginal antipruritic effects occurred regardless of whether participants were informed about the procedure, implying that, if further optimized, open-label behavioral conditioning might be suitable for future applications in clinical practice.

These findings show that conditioning, albeit only marginally, influenced self-reported itch, which is in line with previous findings that show that associative learning mechanisms can influence itch and allergic symptoms (11,14,21,22). Most studies have investigated conditioned exacerbation of allergic responses, whereas evidence for alleviation of itch through associative learning mechanisms is more limited and has only so far been examined in allergic patients (21,22). In patients, it may be especially difficult to ascribe findings exclusively to behavioral conditioning because external influences on learning may also be relevant. For example, natural fluctuations in symptom severity during acquisition of the conditioned response may affect conscious expectancy, due to these fluctuations being interpreted as medication effects. This in turn could influence symptom reporting within both the conditioned and control groups. Resultantly, to reduce the influence of such external factors on conditioning, the current study sought to investigate whether antipruritic effects could be conditioned in healthy volunteers.

Goebel and colleagues (21) had previously found a unique conditioned response for basophil activation in allergic patients, but symptoms reduced regardless of group allocation. Vits and colleagues (22) confirmed these findings and demonstrated symptom reduction for the conditioned and sham-conditioned (placebo) patient groups, compared with a natural history group. This led them to conclude that other cognitive processes, for example, patients’ expectations of benefit, may be relevant. Likewise, the current study provides only limited evidence for the role of conditioning in reducing histamine-induced itch. Some differences between the current study and previous studies can be noted. In the studies of Goebel and colleagues (21) and Vits and colleagues (22), patients reported symptoms at the time of enrollment in the study. In the current study, the sample consisted of nonallergic participants, or allergic participants who had not experienced symptoms for some time before enrollment. Potentially, this may have elicited smaller conditioned responses, as the pharmacological effects of levocetirizine during acquisition may not have been clearly perceived as much as they would be when allergic symptoms were present. Moreover, itch was induced in the final evocation session, to prevent that histamine iontophoresis—which entails the introduction of a foreign chemical substance to the skin (42)—interfered with measurements of conditioned responses for other study outcomes. Although literature indicates that conditioned immunological responses can persist for multiple—potentially even up to 14—evocation moments (39,43,44), it may be possible that some extinction in the conditioned response was already present in the second and third evocation sessions. Future research could investigate whether conditioned effects for itch are stronger at earlier evocation moments, for example, when participants are for the first time reexposed to the CS after the acquisition phase. Alternatively, it may be possible that the antipruritic effects of levocetirizine were too small for experimental histamine-induced itch to be effectively conditioned. Indeed, in the current study, itch reduced from baseline in general, with only marginal differences between the conditioned and control groups (21.3% reduction of itch from baseline in the conditioned groups versus 10.9% reduction in the control groups). Previous evidence dispels the notion that this small difference between groups may be due to failure of the UCS to suppress itch though, because it is demonstrated that levocetirizine has a suppression rate for itch that lies between 62% and 94% (45–47). A similar suppression rate would be expected for levocetirizine in the current study. Future research, however, may want to include a drug control group to confirm this notion and to be able to directly compare conditioned with nonconditioned responses.

Speculatively, the marginal antipruritic conditioned effect in the current study could have emerged through peripheral neurobiological mechanisms, for example, immune-mediated inhibition of pruriceptor neurons (48–50). Such mechanisms have been proposed to underlie systemic behaviorally conditioned immunosuppression (8,51). Alternatively, effects may have emerged through top-down central nervous system antipruritic mechanisms, for example, in case of itch with a neuropathic and psychogenic origin (23,52,53). As an example of central nervous system–mediated itch, itch has been found to be socially contagious in both patients and healthy volunteers (54–56). Future research may aim to clarify through which pathways antipruritic conditioned effects are established.

No conditioning effects were found for spirometry parameters. Literature indicates that pulmonary conditions such as asthma are sensitive to placebo responding (57,58), and antihistamines have been found to have bronchodilatory properties, as shown by their impact on spirometry parameters such as FEV1 (59–62). As such, we explored whether conditioning of antihistamines could affect these parameters as well. The missing data rate in the current study likely affected the findings, however, and the study may have been underpowered for small effects. Moreover, as the sample consisted of healthy volunteers, conditioned responses may be very small because lung function may have already been optimal for a large number of participants. It may be interesting for future research to test the effects of conditioning with antihistamines by experimentally inducing bronchoconstriction, for example, through embedding a histamine bronchial provocation test. No conditioned responses were found for the secondary parameter SCL. HR reduced significantly during evocation for the combined control groups. The time that participants spent sitting in the laboratory was relatively inactive, which likely explains the decrease in HR. For the conditioned groups, HR did not decrease as much in the second and final evocation sessions. Levocetirizine is considered safe for use, and studies show no effects on cardiac safety parameters (63); however, subclinical cardiac effects are often not reported. Moreover, H1-antihistamines—including cetirizine, from which levocetirizine is derived—have been associated with tachycardia and other cardiac adverse effects (64–66). As such, the difference in HR change over time between the conditioned and control groups might speculatively be the result of a conditioned response, although this should be further investigated. In addition, future research may aim to investigate how to enhance the learning process exclusively for the itch-suppressive effects of antihistamines, while avoiding conditioning of adverse effects.

Following the open-label rationale, significantly lower itch was expected during evocation in the open-label group compared with the conditioned-not-evoked group. However, although findings were in the expected direction, itch expectations in the open-label group did not significantly differ from those in the closed-label conditioned and nonconditioned groups. That an open-label rationale may potentially influence expectancy is in line with studies that found that inert pills combined with an open-label rationale can reliably induce placebo effects (28–34). It has also been shown that an open-label rationale regarding the role of expectations in eliciting placebo effects for itch can, in an experimental setting, result in lower expected itch even without providing inert pills (67). The current study extends these findings by preliminary showing an effect of an open-label rationale for a conditioning framework. Potentially, these expectations may help strengthen placebo effects induced by conditioning, although this needs to be investigated more extensively. Demonstrating the efficacy of open-label conditioning could lead toward new therapeutic possibilities and help facilitate utilization of placebo effect mechanisms in clinical practice. It should be noted, though, that the open-label rationale in the current study consisted of multiple components (e.g., an explanation of the conditioning procedure, a suggestion that effects may be as large as the effects of the medication, and a suggestion of reduced itch). Future research may clarify which of these components are essential for inducing expectations of reduced itch, and investigate what other factors help optimize these effects. For example, higher likability and competence of a health care provider have been shown to enhance placebo effects for allergic responses (68). It may be worthwhile to investigate to which extent factors such as likability and competence may influence the efficacy of an open-label rationale as well.

Some limitations of the current study should be considered. Because participants were mostly women, a sex bias cannot be excluded. The experimenter was blinded to group allocation only for the closed-label conditioned and the nonconditioned groups, but not for the open-label conditioned and conditioned-not-evoked groups, because of the differences in the protocol for these latter two groups. Future research may consider having a second, blinded experimenter performing measurements, to prevent that the experimenters’ own expectations influence measurement of the outcome parameters. Second, participants underwent histamine iontophoresis only twice, to prevent interference of histamine application on the conditioned response. As a result, it was not possible to assess conditioned effects for itch on the first and second evocation days, or to assess whether extinction may have taken place. In addition, no drug control group was included in the current study. Moreover, effects of antihistamine administration were not assessed in the acquisition phase because this could influence participants’ conscious expectancy and thus the conditioning procedure. Because the efficacy of levocetirizine for inhibiting the response to histamine has been described in previous literature (45–47,63), we did not directly compare the magnitude of conditioned effects with those of levocetirizine. Future research may consider measuring the response to histamine on multiple testing days and including a drug control group. Finally, all groups received some form of intervention (either conditioning or placebo throughout the study). This may complicate an estimation of a true placebo response, as the idea of receiving an intervention may already influence study outcomes. Moreover, itch was induced twice. Although unlikely to have largely affected study findings—given that the itch stimulus was of short duration and inductions were spaced over 2 weeks apart—habituation cannot be ruled out. Future research may also consider adding a natural history group to control for this.

In conclusion, the current study provides preliminary support for behavioral conditioning of antipruritic effects. In addition, the findings suggest that conditioning may be effective when it is known that a learning paradigm is used. Future research may aim to clarify under which circumstances and on which evocation moments conditioning can be successful in reducing itch. Demonstrating the efficacy of (open-label) conditioning of antipruritic effects may lead toward new therapeutic possibilities. Moreover, further investigation of the content of the open-label rationale may help facilitate utilization of placebo effect mechanisms in clinical practice.

The authors would like to thank the following contributors to the study: Prof. Dr. J. De Houwer (Department of Experimental Clinical and Health Psychology, Ghent University, Belgium) for his advice in designing the open-label instructions regarding the conditioning procedure; M. Los, BSc (Department of Pulmonology, Leiden University Medical Center, the Netherlands) and K.M.C. van Doorn-Hogervorst, BSc (Department of Pulmonology, Leiden University Medical Center, the Netherlands) for the spirometry training and assessment of the quality of spirometry measures taken in the study; and M.C. Lutz, MSc, I.E.M. Kloosterman, MSc, and C. van Leijenhorst, BSc, for their help in collecting the data.

Source of Funding and Conflicts of Interest: The authors declare no conflict of interest. This project was funded by a European Research Council Consolidator Grant 2013 (ID: ERC-2013-CoG-617700_EXPECT HEAL-TH, granted to A.E.). The funders had no role in study design, data collection or analysis, decision to publish, or in writing this manuscript.

REFERENCES

1. Benedetti F, Carlino E, Pollo A. How placebos change the patient’s brain. Neuropsychopharmacology 2011;36:339–54.
2. Colloca L, Miller FG. How placebo responses are formed: a learning perspective. Philos Trans R Soc Lond B Biol Sci 2011;366:1859–69.
3. Bartels DJP, van Laarhoven AIM, van de Kerkhof PCM, Evers AWM. Placebo and nocebo effects on itch: effects, mechanisms, and predictors. Eur J Pain 2016;20:8–13.
4. Peerdeman KJ, van Laarhoven AIM, Peters ML, Evers AWM. An integrative review of the influence of expectancies on pain. Front Psychol 2016;7:1270.
5. Sölle A, Bartholomäus T, Worm M, Klinger R. How to psychologically minimize scratching impulses. Z Psychol 2014;222:140–7.
6. Tekampe J, van Middendorp H, Meeuwis SH, van Leusden JW, Pacheco-Lopez G, Hermus ARMM, Evers AWM. Conditioning immune and endocrine parameters in humans: a systematic review. Psychother Psychosom 2017;86:99–107.
7. Rief W, Bingel U, Schedlowski M, Enck P. Mechanisms involved in placebo and nocebo responses and implications for drug trials. Clin Pharmacol Ther 2011;90:722–6.
8. Hadamitzky M, Sondermann W, Benson S, Schedlowski M. Placebo effects in the immune system. Int Rev Neurobiol 2018;138:39–59.
9. Pacheco-López G, Engler H, Niemi M-B, Schedlowski M. Expectations and associations that heal: immunomodulatory placebo effects and its neurobiology. Brain Behav Immun 2006;20:430–46.
10. Riether C, Doenlen R, Pacheco-López G, Niemi M-B, Engler A, Engler H, Schedlowski M. Behavioural conditioning of immune functions: how the central nervous system controls peripheral immune responses by evoking associative learning processes. Rev Neurosci 2008;19:1–18.
11. Barrett JE, King MG, Pang G. Conditioning rhinitis in allergic humans. Ann N Y Acad Sci 2000;917:853–9.
12. Bartels DJP, van Laarhoven AIM, Haverkamp EA, Wilder-Smith OH, Donders ART, van Middendorp H, van de Kerkhof PCM, Evers AWM. Role of conditioning and verbal suggestion in placebo and nocebo effects on itch. PLoS One 2014;9:e91727.
13. Dark K, Peeke HVS, Ellman G, Salfi M. Behaviorally conditioned histamine release: prior stress and conditionability and extinction of the response. In: Janković BD, Marković BM, Spector NH, editors. Neuroimmune Interactions: Proceedings of the Second International Workshop on Neuroimmunomodulation. New York, NY: New York Academy of Sciences; 1987:578–87.
14. Gauci M, Husband AJ, Saxarra H, King MG. Pavlovian conditioning of nasal tryptase release in human subjects with allergic rhinitis. Physiol Behav 1994;55:823–5.
15. Irie M, Nagata S, Endo Y. Fasting stress exacerbates classical conditioned histamine release in guinea pigs. Life Sci 2002;72:689–98.
16. Irie M, Nagata S, Endo Y. Diazepam attenuates conditioned histamine release in guinea pigs. Int J Psychophysiol 2004;51:231–8.
17. Peeke HV, Dark K, Ellman G, McCurry C, Salfi M. Prior stress and behaviorally conditioned histamine release. Physiol Behav 1987;39:89–93.
18. Russell M, Dark KA, Cummins RW, Ellman G, Callaway E, Peeke HVS. Learned histamine release. Science 1984;225:733–4.
19. Stumpf A, Zerey V, Heuft G, Stander S, Pfleiderer B, Schneider G. Itch perception and skin reactions as modulated by verbal suggestions: role of participant’s and investigator’s sex. Acta Derm Venereol 2016;96:619–23.
20. van Laarhoven AIM, Vogelaar ML, Wilder-Smith OH, van Riel PLCM, van de Kerkhof PCM, Kraaimaat FW, Evers AWM. Induction of nocebo and placebo effects on itch and pain by verbal suggestions. Pain 2011;152:1486–94.
21. Goebel MU, Meykadeh N, Kou W, Schedlowski M, Hengge UR. Behavioral conditioning of antihistamine effects in patients with allergic rhinitis. Psychother Psychosom 2008;77:227–34.
22. Vits S, Cesko E, Benson S, Rueckert A, Hillen U, Schadendorf D, Schedlowski M. Cognitive factors mediate placebo responses in patients with house dust mite allergy. PLoS One 2013;8:e79576.
23. Leslie TA. Itch. Medicine 2013;41:367–71.
24. Thangam EB, Jemima EA, Singh H, Baig MS, Khan M, Mathias CB, Church MK, Saluja R. The role of histamine and histamine receptors in mast cell–mediated allergy and inflammation: the hunt for new therapeutic targets. Front Immunol 2018;9:1873.
25. Enck P, Bingel U, Schedlowski M, Rief W. The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov 2013;12:191–204.
26. Evers AWM, Colloca L, Blease C, Annoni M, Atlas LY, Benedetti F, Bingel U, Buchel C, Carvalho C, Colagiuri B, Crum AJ, Enck P, Gaab J, Geers AL, Howick J, Jensen KB, Kirsch I, Meissner K, Napadow V, Peerdeman KJ, Raz A, Rief W, Vase L, Wager TD, Wampold BE, Weimer K, Wiech K, Kaptchuk TJ, Klinger R, Kelley JM. Implications of placebo and nocebo effects for clinical practice: expert consensus. Psychother Psychosom 2018;87:204–10.
27. Blease C, Colloca L, Kaptchuk TJ. Are open-label placebos ethical? Informed consent and ethical equivocations. Bioethics 2016;30:407–14.
28. Carvalho C, Caetano JM, Cunha L, Rebouta P, Kaptchuk TJ, Kirsch I. Open-label placebo treatment in chronic low back pain: a randomized controlled trial. Pain 2016;157:2766–72.
29. Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, Singer JP, Kowalczykowski M, Miller FG, Kirsch I, Lembo AJ. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One 2010;5:e15591.
30. Kelley JM, Kaptchuk TJ, Cusin C, Lipkin S, Fava M. Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychother Psychosom 2012;81:312–4.
31. Locher C, Frey Nascimento A, Kirsch I, Kossowsky J, Meyer A, Gaab J. Is the rationale more important than deception? A randomized controlled trial of open-label placebo analgesia. Pain 2017;158:2320–8.
32. Sandler AD, Glesne C, Bodfish JW. Conditioned placebo dose reduction: a new treatment in attention-deficit hyperactivity disorder? J Dev Behav Pediatr 2010;31:369–75.
33. Schaefer M, Harke R, Denke C. Open-label placebos improve symptoms in allergic rhinitis: a randomized controlled trial. Psychother Psychosom 2016;85:373–4.
34. Schaefer M, Sahin T, Berstecher B. Why do open-label placebos work? A randomized controlled trial of an open-label placebo induction with and without extended information about the placebo effect in allergic rhinitis. PLoS One 2018;13:e0192758.
35. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013;310:2191–4.
36. Albring A, Wendt L, Ober K, Engler H, Freundlieb C, Witzke O, Kribben A, Schedlowski M. Behavioral conditioning and cognitive expectation in placebo-induced immunosuppression in humans. Neuroimmunomodulation 2011;18:361.
37. Goebel MU, Trebst AE, Steiner J, Xie YF, Exton MS, Frede S, Canbay AE, Michel MC, Heemann U, Schedlowski M. Behavioral conditioning of immunosuppression is possible in humans. FASEB J 2002;16:1869–73.
38. Grigoleit J-S, Kullmann JS, Winkelhaus A, Engler H, Wegner A, Hammes F, Oberbeck R, Schedlowski M. Single-trial conditioning in a human taste—endotoxin paradigm induces conditioned odor aversion but not cytokine responses. Brain Behav Immun 2012;26:234–8.
39. Wirth T, Ober K, Prager G, Vogelsang M, Benson S, Witzke O, Kribben A, Engler H, Schedlowski M. Repeated recall of learned immunosuppression: evidence from rats and men. Brain Behav Immun 2011;25:1444–51.
40. Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS Scales. J Pers Soc Psychol 1988;54:1063–70.
41. Spielberger CD. Manual for the State-Trait Anxiety Inventory. Revised ed. Palo Alto, CA: Consulting Psychologists Press; 1983.
42. Fostini AC, Girolomoni G. Experimental elicitation of itch: evoking and evaluation techniques. J Dermatol Sci 2015;80:13–7.
43. Albring A, Wendt L, Benson S, Nissen S, Yavuz Z, Engler H, Witzke O, Schedlowski M. Preserving learned immunosuppressive placebo response: perspectives for clinical application. Clin Pharmacol Ther 2014;96:247–55.
44. Smits RM, Veldhuijzen DS, Wulffraat NM, Evers AWM. The role of placebo effects in immune-related conditions: mechanisms and clinical considerations. Expert Rev Clin Immunol 2018;14:761–70.
45. Clough GF, Boutsiouki P, Church MK. Comparison of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin. Allergy 2001;56:985–8.
46. Karppinen A, Brummer-Korvenkontio H, Petman L, Kautiainen H, Hervé JP, Reunala T. Levocetirizine for treatment of immediate and delayed mosquito bite reactions. Acta Derm Venereol 2006;86:329–31.
47. Passalacqua G, Canonica GW. A review of the evidence from comparative studies of levocetirizine and desloratadine for the symptoms of allergic rhinitis. Clin Ther 2005;27:979–92.
48. Voisin T, Bouvier A, Chiu IM. Neuro-immune interactions in allergic diseases: novel targets for therapeutics. Int Immunol 2017;29:247–61.
49. Ji RR. Neuroimmune interactions in itch: do chronic itch, chronic pain, and chronic cough share similar mechanisms? Pulm Pharmacol Ther 2015;35:81–6.
50. Krajnik M, Zylicz Z. Understanding pruritus in systemic disease. J Pain Symptom Manage 2001;21:151–68.
51. Schedlowski M, Pacheco-López G. The learned immune response: Pavlov and beyond. Brain Behav Immun 2010;24:176–85.
52. Grundmann S, Ständer S. Chronic Pruritus: Clinics and Treatment. Ann Dermatol 2011;23:1–11.
53. Yosipovitch G, Samuel LS. Neuropathic and psychogenic itch. Dermatol Ther 2008;21:32–41.
54. Holle H, Warne K, Seth AK, Critchley HD, Ward J. Neural basis of contagious itch and why some people are more prone to it. Proc Natl Acad Sci U S A 2012;109:19816–21.
55. Papoiu ADP, Wang H, Coghill RC, Chan YH, Yosipovitch G. Contagious itch in humans: a study of visual ‘transmission’ of itch in atopic dermatitis and healthy subjects. Br J Dermatol 2011;164:1299–303.
56. Schut C, Grossman S, Gieler U, Kupfer J, Yosipovitch G. Contagious itch: what we know and what we would like to know. Front Hum Neurosci 2015;9:1–6.
57. Janssens T, Caris E, Van Diest I, Van den Bergh O. Learning to detect triggers of airway symptoms: the role of illness beliefs, conceptual categories and actual experience with allergic symptoms. Front Psychol 2017;8:1–10.
58. Kemeny ME, Rosenwasser LJ, Panettieri RA, Rose RM, Berg-Smith SM, Kline JN. Placebo response in asthma: a robust and objective phenomenon. J Allergy Clin Immunol 2007;119:1375–81.
59. Nelson HS. Prospects for antihistamines in the treatment of asthma. J Allergy Clin Immunol 2003;112:S96–100.
60. Borade PS, Ballary CC, Currie GP, Lee DKC. Modern H1-antihistamines in asthma. Drug Discov Today Ther Strateg 2006;3:253–9.
61. Spector SL, Nicodemus CF, Corren J, Schanker HM, Rachelefsky GS, Katz RM, Siegel SC. Comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-to-moderate asthma. J Allergy Clin Immunol 1995;96:174–81.
62. Wilson AM. Are antihistamines useful in managing asthma? Curr Opin Allergy Clin Immunol 2002;2:53–9.
63. Hair PI, Scott LJ. Levocetirizine. Drugs 2006;66:973–96.
64. Golightly LK, Greos LS. Second-generation antihistamines: actions and efficacy in the management of allergic disorders. Drugs 2005;65:341–84.
65. Raschi E, Poluzzi E, Salvo F, Koci A, Suling M, Antoniazzi S, Perina L, Hazell L, Moretti U, Sturkenboom M, Garbe E, Pariente A, De Ponti F. The contribution of national spontaneous reporting systems to detect signals of torsadogenicity: issues emerging from the ARITMO project. Drug Saf 2016;39:59–68.
66. Simons FE. Advances in H1-antihistamines. N Engl J Med 2004;351:220–17.
67. Meeuwis SH, van Middendorp H, Veldhuijzen DS, van Laarhoven AIM, De Houwer J, Lavrijsen APM, Evers AWM. Placebo effects of open-label verbal suggestions on itch. Acta Derm Venereol 2018;98:268–74.
68. Howe LC, Goyer JP, Crum AJ. Harnessing the placebo effect: exploring the influence of physician characteristics on placebo response. Health Psychol 2017;36:1074–82.
Keywords:

placebo effects; behavioral conditioning; expectancy; histamine; itch; pruritus; ANCOVA = analysis of covariance; CS = conditioned stimulus; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; GLM = general linear model; HR = heart rate (in beats per minute); NRS = Numeric Rating Scale; SCL = skin conductance level; UCS = unconditioned stimulus

Supplemental Digital Content

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.