Psychological mechanisms of offset analgesia: The effect of expectancy manipulation

Tibor M Szikszay; Waclaw M Adamczyk; Janina Panskus; Lotte Heimes; Carolin David; Philip Gouverneur; Kerstin Luedtke

doi:10.1371/journal.pone.0280579

. 2023 Jan 17;18(1):e0280579. doi: 10.1371/journal.pone.0280579

Psychological mechanisms of offset analgesia: The effect of expectancy manipulation

Tibor M Szikszay ^1,^*,^#, Waclaw M Adamczyk ^1,^2,^#, Janina Panskus ¹, Lotte Heimes ¹, Carolin David ¹, Philip Gouverneur ³, Kerstin Luedtke ¹

Editor: Kelly Naugle⁴

PMCID: PMC9844857 PMID: 36649306

Abstract

A frequently used paradigm to quantify endogenous pain modulation is offset analgesia, which is defined as a disproportionate large reduction in pain following a small decrease in a heat stimulus. The aim of this study was to determine whether suggestion influences the magnitude of offset analgesia in healthy participants. A total of 97 participants were randomized into three groups (hypoalgesic group, hyperalgesic group, control group). All participants received four heat stimuli (two constant trials and two offset trials) to the ventral, non-dominant forearm while they were asked to rate their perceived pain using a computerized visual analogue scale. In addition, electrodermal activity was measured during each heat stimulus. Participants in both intervention groups were given a visual and verbal suggestion about the expected pain response in an hypoalgesic and hyperalgesic manner. The control group received no suggestion. In all groups, significant offset analgesia was provoked, indicated by reduced pain ratings (p < 0.001) and enhanced electrodermal activity level (p < 0.01). A significant group difference in the magnitude of offset analgesia was found between the three groups (F_[2,94] = 4.81, p < 0.05). Participants in the hyperalgesic group perceived significantly more pain than the hypoalgesic group (p = 0.031) and the control group (p < 0.05). However, the electrodermal activity data did not replicate this trend (p > 0.05). The results of this study indicate that suggestion can be effective to reduce but not increase endogenous pain modulation quantified by offset analgesia in healthy participants.

Introduction

Endogenous pain modulation has been proposed and is discussed as a leading feature of the nociceptive system that can promote or protect the individual against the transition from acute to chronic pain [1, 2]. In general, pain modulation can be assessed through experimental paradigms which are believed to reflect complex inhibitory and faciliatory mechanisms within the neuroaxis [3]. Thus, within the peripheral and central nervous system, a variety of individual transmitters and specific receptor types are involved in the modulation and expression of descending inhibition and facilitation [4]. In the central nervous system, pain can be modulated by cognitive, affective and motivational factors [5] including beliefs and expectations [6]. Furthermore, the efficiency of these modulatory pathways can be assessed in the laboratory setting, using paradigms such as conditioned pain modulation (CPM: the “pain inhibits pain”) [2] and/or offset analgesia (OA).

Offset analgesia can be defined as a disproportionally large pain decrease after a minor noxious stimulus intensity reduction [7]. This test procedure is discussed to indicate the efficiency of the descending inhibitory pain modulation system in humans [8]. For almost 20 years, numerous studies have attempted to identify the processes underlying OA, but the physiological mechanisms have not yet been fully understood. Both peripheral [9–11], spinal [12] and supra-spinal mechanisms [9, 13–17] have been shown to contribute to OA. However, few experimental procedures in the past effectively modulated the OA effect. For instance, the modulatory influence of primary afferents [11, 18] or secondary noxious stimuli [19] are exceptions rather than common findings expanding our knowledge of OA. In contrast, all pharmacological attempts failed to affect OA [20].

Interestingly, psychological interventions have never been used in the context of OA. It is of clinical interest, whether psychological processes influence endogenous pain modulation, especially since—amongst others- hypo- or hyperalgesic suggestion have been shown to effectively decrease [21] or increase [22] pain perception, respectively. For example, it has been demonstrated that by administering a hyperalgesic suggestion prior the application of a noxious stimulus, healthy subjects felt more pain [23]. The putative mechanism of such an intervention relates to expectations [24], which has already been observed in CPM experiments [25, 26] but not yet in OA.

This experiment attempted to influence the magnitude of OA by manipulating participants’ expectations using suggestions. In this study, suggestions were used to modulate OA selectively, that is, by changing the pain response in the final temperature phase of the paradigm. Therefore, the á priori hypothesis implied that suggestion would influence the OA effect in a bidirectional manner, i.e., analgesia was expected to be increased or decreased, respectively, compared to a control group that was not exposed to any form of suggestion.

Materials and methods

Study design

This experimental study was conducted as a randomized controlled trial in which healthy, pain-free participants were randomly divided (counterbalanced) into two intervention groups and one control group. Both intervention groups received either a hypoalgesic or a hyperalgesic suggestion related to the pattern of the subsequently applied heat pain within an OA paradigm. The control group received no suggestion. All participants received the identical information about the exact temperature course of the heat stimuli beforehand. In order to perform the suggestions as authentically as possible, a cover story was told to all participants at the beginning of the study. All participants were blinded to the true purpose of the study. The study was previously approved by the ethics committee of the University of Lübeck (file number: 21–028) and pre-registered in the Open Science Framework (https://osf.io/69eyp). All participants provided oral and written informed consent. An overview of the study design is provided in Fig 1.

Fig 1 — Before randomization, participants were instructed and a cover story was provided. Participants were told that in this study, changes in electrodermal activity (EDA) would be assessed as a measure of the autonomic nervous system during experimental heat stimuli and used to predict the perception of pain (cover story). Participants were assigned to either i) the hypoalgesic group with suggestion towards profound hypoalgesia following the temperature reduction, ii) the hyperalgesic group with verbal suggestion towards hyperalgesia following the temperature reduction (see the example above), or iii) the control group with no intervention. Regardless of the group assignment participants were exposed to two offset and two constant trials provided in a counterbalanced manner.

Study population

Healthy, pain-free participants aged 18 to 65 years were recruited on the campus of the University of Lübeck. All participants had to subjectively confirm that they were healthy. Furthermore, participant had no cardiovascular, systemic, psychiatric or neurological disease. Furthermore, all participants were excluded if they had a history of chronic pain (> 3 months) within the last 2 years or had experienced pain (including headache, toothache, muscle soreness, etc.) within the last week prior to study participation. In addition, the use of medication, excluding contraceptives, in the last 48 hours was an exclusion criterion. Furthermore, participants were asked not to drink alcohol, exercise, or take pain medication for 24 hours prior to participation in the study and not to drink coffee or smoke cigarettes for 4 hours prior to study participation.

Equipment

A Pathway CHEPS (Contact Heat -Evoked Potential Stimulator) with a contact area of 27mm diameter was used for the application of the heat stimuli (Medoc, Ramat Yishai, Israel). The thermode was attached to the non-dominant volar forearm approximately 10 cm below the elbow using a blood pressure cuff with a pressure of 25 mmHg. A computerized visual analog scale hardware device (COVAS; with the range 0 = "no pain" to 100 = "most tolerable pain") was used for continuous assessment of pain intensity (Medoc, Ramat Yishai, Israel). Furthermore, during heat stimuli, electrodermal activity (EDA; respiBAN Professional, Plux, Lisbon, Portugal) was measured using two Ag/AgCl hydrogel electrodes (Covidien / Kendall, Dublin, Ireland) at the medial phalanx of index and middle finger of the non-dominant arm (sampling rate of 1000 Hz, PLUX Wireless Biosignals, S.A., Portugal). Electrodermal activity depends on sweat secretion, which is closely related to autonomic nervous system activity [27]. EDA was used to test, if verbal suggestion influences physiological responses and if EDA can be used as an objective marker for OA.

Experimental heat stimulation

Two constant trials (CT) and two offset trials (OT) were performed on the non-dominant volar forearm, so that the participants were presented with a total of four heat stimuli. The order in which trials were presented was randomized in a counterbalanced fashion. A two-minute pause was kept between each stimulus, during which the thermode was moved on the forearm by a few centimeters. The temperature’s rise and fall rate for all heat stimuli was 15°C/second. During CT, the temperature increased from a baseline level of 35°C to 46°C and remained constant for 40 seconds before returning to the baseline level. During OT, the temperature first increased to 46°C (T1) for 10 seconds, then increased to 47°C (T2) for 10 seconds, and finally decreased again to 46°C (T3) lasting 20 seconds. The temperature pattern of the two trials can be seen in Fig 1. These figures were shown to the participants before the application of the heat stimuli. During the application of the heat stimuli, participants were asked to rate perceived pain continuously and as precisely using the COVAS.

Suggestion

The participants were provided with a cover story. It was explained that the aim of the study was to find out whether the subjective sensation of pain could be "read out" from the physiological reaction of the body (skin conductance) and thus be predicted. A cover story was necessary to also justify the introduction of suggestion as credibly as possible without participants becoming skeptical or biased.

The hypoalgesic or hyperalgesic groups received suggestions about the expected pain pattern and the pain intensity of the applied heat stimuli. The hypoalgesic group received a suggestion to enhance the effect of OA and adaptation to CT, i.e., to reduce pain perception. The hyperalgesic group, on the other hand, received a suggestion, which was intended to reduce the effect of OA and adaptation to CT, i.e., to increase pain perception. The expected pain pattern was manipulated verbally (S1 File) and supported with the graphical presentation of the assumed pain pattern (S1 Fig) and took place directly after the explanation of the temperature gradients, i.e. immediately before application of the respective heat stimulus.

Questionnaires

Before starting the heat application, participants were asked to complete several questionnaires: The Patient Health Questionnaire (PHQ-9) includes nine questions about depression [28]. While the Pain Vigilance and Awareness Questionnaire (PVAQ) measures pain perception and pain awareness [29], the Pain Sensitivity Questionnaire (PSQ) can be used to determine the subject’s pain sensitivity [30]. The State-Trait Anxiety Inventory-SKD (STAI-SKD) was also collected to determine the participant’s current state anxiety before the experiment [31]. The Social Desirability Scale-17 (SDS-17) was used to measure the participant’s social desirability [32]. Furthermore, the Mindful Attention and Awareness Scale (MAAS) was used to measure dispositional mindfulness [33] and the Life-Orientation Test (LOT-R) was used to measure individual differences between optimism and pessimism based on personality traits [34].

Manipulation check

To assess the effect of suggestion on pain perception during the OA paradigm, a manipulation check was performed immediately after pain assessment. The following was asked separately for OT and CT: “Please try to recall the moment immediately after receiving heat stimuli. Did you perceive the pain as in the previously displayed figures?” Participants provided a binary (yes vs. no) response.

Statistical analysis

In the absence of studies investigating OA and verbal suggestion, a meta-analysis examining the effect of verbal suggestion on general pain perception was used to calculate the sample size [22]. With the lowest reported effect size of 0.66 (Cohen’s d), a power of 80%, and an alpha of 0.05, a total number of 30 participants in each group (total = 90) was required (G*Power, University of Düsseldorf [35]) to demonstrate a significant difference between experimental and control groups.

COVAS data from the Medoc software and the EDA signals were synchronized. The time-series data were down-sampled to a frequency of 1 Hz by using the “resample” function of the python package “Pandas” (Python 3.9.7, pandas 1.4.2). Here, multiple data points are aggregated and replaced by their average. No further preprocessing steps were performed. All other statistical analyses were performed using the IBM Statistical Package for Social Science (SPSS version 26, Armonk, NY). The three groups were tested for group differences using age, BMI, sex, dominant hand, and questionnaire data. One-way analysis of variance (ANOVA), Kruskal-Wallis tests, or chi-square tests were used accordingly.

Differences between the groups in their initial pain response at the beginning of the heat stimuli were examined. For this purpose, pain ratings were averaged from the last 5 seconds of the T1 and T2 interval. Separately for OTs and CTs (mean value of the two CTs and two OTs) one-way ANOVAs were used to analyze differences between the groups. The primary outcome in this study was the magnitude of the pain response to the T3 interval (OT). To ensure that the magnitude of the OA effect was not under- or overestimated, the mean of 10 seconds centered in the T3 interval (secs. 25–34) were extracted. The 5 seconds at the beginning of the interval were not included, because the pain may still decrease during this time, and the 5 seconds at the end of the interval were not included, because the analgesic effect of OA usually decreases after approximately 15 seconds [36]. OT and CT (again mean of the two CTs and OTs) were analyzed separately, as both trials were also separately attempted to be influenced by suggestion. However, dependent t-tests were used to demonstrate whether the pain response and EDA signal from CT were significantly different from OT in each of the groups and thus whether there was an OA effect. To examine the effect of suggestion on OT and CT, a one-way ANOVA was conducted comparing the T3 interval pain response of the three groups as described. An additional method of analysis calculating the percentage difference of the maximum pain ratings for T2 and the minimum pain rating for T3 is included in the supporting information (S2 File).

The EDA data were analyzed according to identical principles as the pain response. As part of a secondary analysis of the EDA data in the control group, an ANOVA was performed with the within factor “interval” (T1, T2, T3) and the within factor “trial” (OT, CT). Furthermore, a dependent t-test was used to examine whether the magnitude of the EDA magnitude differed within the temperature increase/decrease (i.e. comparing the EDA magnitude from the difference of T2 and T1 with the difference of T2 and T3).

If statistically significant main or interaction effects were detected, Bonferroni corrected post-hoc t tests were conducted. The correlations between the pain response of the T3 (OT) and the previously described questionnaires were calculated using the Spearman coefficient. No data were missing at the time of analysis. A p value of less than 0.05 was considered significant for all comparisons.

Results

A total of 97 participants (hypoalgesic n = 32, hyperalgesic n = 33, control group n = 32) were included in this study. No significant differences were found between groups regarding baseline characteristics (Table 1). The raw data are presented in the supporting information (S3 File).

Table 1. Participant characteristics for each group.

	Hypoalgesic (n = 32)	Hyperalgesic (n = 33)	Control (n = 32)	p
Age $\bar{x}$ (SD)	29.7 (12.2)	25.6 (9.0)	28.7 (11.4)	0.30 ^a
BMI $\bar{x}$ (SD)	23.0 (2.3)	23.1 (2.4)	22.9 (3.2)	0.97 ^a
Female n (%)	17 (53.1)	16 (48.5)	20 (62.5)	0.51 ^b
Right-handed n (%)	30 (93.8)	30 (90.9)	27 (84.4)	0.45 ^b
PHQ9 M (IQR)	3.0 (1.0; 4.0)	2 (2.0; 4.5)	3 (1.3; 4.0)	0.95 ^c
PVAQ M (IQR)	41.5 (34.0; 49.8)	38 (29.0; 46.6)	36.5 (28.0; 48.0)	0.32 ^c
PSQ M (IQR)	3.2 (2.5; 4.4)	3.5 (2.3; 4.2)	2.8 (2.3; 3.7)	0.44 ^c
STAIT-SKD M (IQR)	6 (5.0; 7.0)	6 (5.0; 7.0)	6 (5.0; 7.0)	0.76 ^c
SDS-17 M (IQR)	12 (11.0; 14.0)	12 (10.0; 13.5)	10.5 (8.0; 13.0)	0,08 ^c
MAAS M (IQR)	65.0 (59.0; 72.0)	66.0 (62.5; 71.5)	66.0 (56.3; 72.8)	0.72 ^c
LOT-R M (IQR)	19.0 (16.3; 21,8)	19.0 (17.0; 21.0)	19.0 (16.3; 21.0)	0.90 ^c

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$\bar{x}$ : mean SD; Standard deviation; M: Median; IQR: Interquartile range; PHQ9: Patient Health Questionnaire; PVAQ: Pain Vigilance and Awareness Questionnaire; PSQ: Pain Sensitivity Questionnaire; STAIT-SKD: State-Trait-Anxiety-Inventory-SKD; SDS-17: Social Desirability Scale-17; MAAS: Mindful Attention and Awareness Scale, LOT-R: Life-Orientation-Test

^a Analysis of variance

^b Chi²-Test

^c Kruskal-Wallis-Test.

Mean pain curves and averaged pain from T3 intervals are presented in Figs 2 and 3, respectively. No significant differences were found between all groups regarding the T1 interval for either OT (F_{(2, 94)} = 2.48, p = 0.09, η²_p = 0.06) or CT (F_{[2, 94]} = 1.81, p = 0.17, η²_p = 0.04). Dependent t-tests showed that OT regarding the T3 interval was significantly different from CT in the pain ratings (hypoalgesic: t_[31] = 6.3, p < 0.001, d_z = 1.12; hyperalgesic: t_[32] = 5.8, p < 0.001, d_z = 1.01; control: t_[31] = 7.1, p < 0.001, d_z = 1.25) as well as EDA (hypoalgesic: t_[31] = 4.1, p < 0.001, d_z = -0.71; hyperalgesic: t_[32] = 4.5, p < 0.001, d_z = -0.78; control: t_[31] = 3.5, p < 0.001, d_z = -0.61) in all groups, indicating an OA effect within each of the groups.

Fig 2 — Pain ratings in offset analgesia (left) and constant trials (right). Note that in offset analgesia trials, pain was disproportionally reduced during the last 20s of thermal stimulation assessed via a computerized visual analog scale (COVAS). Hyperalgesic suggestion inhibited the development of profound analgesia present in the control as well as the hypoalgesic group. Suggestion affected constant trials in a similar fashion. Bold curves represent mean pain whereas shaded zones are standard errors of the mean (SEM).

Fig 3 — Within- and between-group effects for pain assessed via a computerized visual analog scale (COVAS, left) and electrodermal activity (EDA, right). Offset analgesia was reduced in the hyperalgesic group as reflected by a less pronounced difference in pain (averaged of 25-34s interval) between offset trials (OT) and constant trials (CT). Upper comparisons denote between-group comparisons: The hyperalgesic group experienced more pain than the control and hypoalgesic groups. Lower comparisons denote within-group comparisons for OT and CT. Error bars represent standard errors of the mean (SEM), * indicates a significant difference at p < 0.05, *** p < 0.001.

During OT, a significant difference for the factor “group” was found between the three groups in pain ratings at T3 (F_{[2, 94]} = 4.81, p = 0.01, η²_p = 0.10). Bonferroni-corrected post-hoc t-tests showed significantly greater pain in the hyperalgesic group than in both the hypoalgesic (p = 0.03) and control (p = 0.02) groups. In contrast, no significant difference was found between the hypoalgesic and the control group (p = 1.00, see comparisons on Fig 3). Results for an additional method of analysis are presented in the supporting information (S2 File). Regarding the CT (T3 interval), no significant difference was shown between all groups (F_{[2, 94]} = 2.08, p = 0.13, η²_p = 0.13), indicating that the verbal suggestion affected OA trials in the hyperalgesic group and not constant trials. Furthermore, no significant difference was shown between the groups regarding EDA in the T3 time interval, neither for OT (F_{[2, 94]} = 0.98, p = 0.38, η²_p = 0.02) nor for CT (F_{[2, 94]} = 0.91, p = 0.40, η²_p = 0.02, Figs 3 and 4).

Fig 4 — Electrodermal activity (EDA) in offset analgesia (left) and constant trials (right). Compared to constant trials, offset analgesia produced paradoxically higher EDA levels during the T3 interval. Bold curves represent mean pain whereas shaded zones are standard errors of the mean (SEM). Vertical markers separate T1, T2 and T3 intervals.

After completion of the study, 70.1% (n = 68) of the participants stated that they perceived pain during OT that was in line with the provided suggestion. Pain response consistent with the provided suggestion was confirmed by 90.6% (n = 29) of the participants in the hypoalgesic group, but only 21.2% (n = 7) in the hyperalgesic group. A significant difference between groups was observed (χ²_{[1, 65]} = 31.7, p < 0.001, Φ = 0.70). 74.2% of participants (n = 72) confirmed this for the CT. Thereby, 75.0% (n = 24) confirmed this in the hypoalgesic, but only 48.5% (n = 16) in the hyperalgesic group (χ²_{[1, 65]} = 4.8, p = 0.03, Φ = 0.27).

Secondary analyses of the EDA data within the control group revealed a significant interaction between the factors “interval” (T1, T2, T3) and “trial” (OT, CT) (F_{[1.4, 62]} = 9.0, p = 0.002, η²_p = 0.23). Bonferroni-corrected post-hoc comparisons showed significant differences between OT and CT for the interval T2 (p <0.001) and T3 (p = 0.002), but not for the interval T1 (p = 0.42). Furthermore, within the trial OT significant differences were found between T1 and T2 (p = 0.002) and between T2 and T3 (p < 0.001), but not between T1 and T3 (p = 1.00). A dependent t-test showed that the EDA magnitude of the increase from T1 to T2 did not differ from the magnitude of the reduction from T2 to T3 (T_[31] = 0.21, p = 0.84, d_z = 0.04).

No significant correlations were found between the previously described questionnaires and the T3 pain response (OT) in the hypoalgesic group as well as in the control group (p > 0.05, r < 0.3). However, in the hyperalgesic group a significant correlation with the LOT-R was shown (r = -0.45, p < 0.01), which can be attributed mainly to optimism characteristics (optimisms score: r = -0.55, p < 0.01) and not to pessimism characteristics (pessimisms score: r = 0.27 (p = 0.13). All correlation results are presented in the supporting information (S1 Table).

Discussion

In summary, it can be concluded that OA was provoked in all groups, independent of the suggestion manipulation. However, the pain response but not the EDA response during an OA paradigm was influenced by visually reinforced verbal suggestion in healthy participants via hyperalgesic suggestion, but not via hypoalgesic suggestion.

Expectancy mechanism

To the best of our knowledge, this is the first study that has attempted to influence OA using suggestion. However, similar results have already been reported for studies that attempted to influence outcomes using other paradigms to quantify endogenous pain modulation by using suggestion. For example, a similar conclusion was reported by Vaegter et al. (2020) which attempted to influence exercise-induced hypoalgesia (EIH) using suggestion [37]. In that study, EIH was defined as an increased pain threshold and pain tolerance induced by performing a single exercise routine. It was found that volunteers who received a negative suggestion prior to exercise, experienced hyperalgesia instead of EIH. Furthermore, studies found that CPM can also be influenced by suggestions and thereby altered expectation [26, 38]. In CPM, the pain response to a painful test stimulus is inhibited by the application of a distant painful conditioning stimulus [39]. Goffaux et al. (2007) studied 20 healthy volunteers regarding their pain perception during the CPM paradigm while they were given different verbal suggestions about the expected pain process [38]. While the hypoalgesic group experienced profound analgesia, this was absent in the hyperalgesic group. Moreover, Bjørkedal and Flaten (2012) also found an effect of verbal suggestion on pain perception in the CPM paradigm [26]. It should be noted, however, that OA is not based on the same mechanisms as CPM and EIH, making them not directly comparable. For example, CPM, unlike OA, can be influenced by ketamine [40], and the two paradigms have underlying distinct brain mechanisms [41]. In addition, other studies have shown that there is no correlation between OA and EIH [42] or OA and CPM [41, 43], also suggesting individual mechanisms of these pain modulation phenotypes. However, based on these similar results for CPM, EIH, and OA, it is reasonable to assume that altered expectations manipulated by suggestion influence endogenous pain modulation processes as quantified via various paradigms.

In general, it can be assumed that suggestion influences OA, since brain activity during OA overlaps with the activity during placebo analgesia [8, 44]. Previous studies have shown that especially the activation of the rostral anterior cingulate cortex (rACC) and the dorsolateral prefrontal cortex (DLPC) play a major role in placebo analgesia [45, 46]. They are both functionally connected with the periaqueductal gray and the rostral ventromedial medulla (PAG-RVM system), which can send inhibitory projections to the spine and thereby elicit a diffuse analgesic response [47]. Increased activation of the DLPC and PAG-RVM circuits were also found during OA [13, 15, 41], suggesting that the mechanisms of placebo analgesia and OA may be similar. However, this is contradicted by the results that hypoalgesic suggestion did not produce increased pain reduction in OA in this study. This can be explained by the fact, that previous studies have shown that placebo analgesia is mediated primarily by increased release of endogenous opiates [48], whereas OA has been shown to be opioid-independent [49]. For example, placebo analgesia can be blocked by the opioid antagonist naloxone [50], whereas naloxone, on the other hand, has no effect on the magnitude of OA [49]. One study has found that nocebo hyperalgesia is mediated by the neurotransmitter cholecystokinin (CCK) [51]. However, the effect of CCK on OA has not yet been studied, although it is relevant since the hyperalgesic manipulation could have influenced the OA.

Interestingly, no significant effect of the suggestion was found on CT in this study. Pain perception in the T3 interval of the CT was neither increased nor decreased. This result is in contrasts with other reports because, in principle, both hypo- or hyperalgesic suggestion have been found in previous studies to influence a wide variety of noxious stimuli [21, 52]. For example, the study by van Laarhoven et al. (2011) found an effect of hyperalgesic verbal suggestion on pain perception in healthy women. However, this study did not use tonic heat stimuli, but mechanical and electrical stimuli [23]. The methodology of other studies also differed in many ways from the present study. For example, studies often used other stimulus modalities (e.g., cold, electric shocks, ischemic pain), or did not use verbal and visual suggestion but used either conditioning alone or a combination of conditioning and suggestion to influence pain perception [21, 52]. Furthermore, no study was found that investigated the effect of verbal and visual suggestion on a constant (tonic) heat stimulus, as done in this study. However, one explanation for the differences in influences on CT versus OT could be the difference in physiological processing. It is suggested that pain adaptation to a moderate, constant heat stimulus is primarily mediated by peripheral mechanisms [53–55]. In comparison, both peripheral and central mechanisms are known to shape OA [8]. Since peripheral mechanisms cannot be influenced by suggestion, this could be a possible explanation for the lack of influence on CT. At the same time, the shown suggestibility during OT could support the assumption that OA is primarily a central phenomenon, as pain perception was modulated by expectancy, here. Further studies comparing the suggestibility of responses to OT and CT are needed to draw further conclusions about the underlying mechanisms.

As a limitation, suggestions might not have been fully successful, as shown by the results of the manipulation check. Although the majority (70.1%) of the subjects reported that they perceived a pain response during OT according to the prior given suggestion. However, in contrast to the hypoalgesic group (90.6%), only 21.2% in the hyperalgesic group confirmed a pain response as suggested. Thus, it can be assumed that one reason for this may be the exceptionally robust analgesia during the OA paradigm. Thus, these results show that OA can be influenced only unidirectionally, being more likely to be enhanced but more difficult to be inhibited.

Physiological mechanisms

So far, physiological measurements taken during OA included functional magnetic resonance imaging [12, 13, 15, 17, 41], electroencephalography [56] and functional near-infrared spectroscopy [57]. To the best of our knowledge, this is the first experiment which recorded EDA during OA. This was done for the following reasons: Firstly, OA has been shown to be mediated by the activation of brain areas associated with the regulation of autonomic reactivity [13, 15, 58, 59], thus we aimed to capture this variable continuously to test if OA measurements behaviorally overlap with physiological responses. Secondly, we aimed to investigate if verbal suggestion alters both, subjective and objective outcomes during an OA paradigm.

Interestingly, results of this study showed that, contrary to our prediction, EDA responses to OT were not decreased alongside pain perception. In turn, the increase of the temperature during a T2 interval significantly elevated the EDA level which persisted during the T3 interval, whereas the pain response was reduced. Indeed, a lowered pain intensity overlapped with higher EDA level in offset compared to constant trial. It can be suggested that the higher stimulus in T2 of the OT activates the descending pain inhibition pathways and therefore inhibits pain. In fact, the EDA level during CT gradually decreased over-time which was, in general, associated with higher pain compared to OTs. During OA, endogenous modulatory mechanisms have been shown to be activated [9], which are believed to be driven by PAG activation [13]. PAG is an anatomic structure with multiple nociceptive projections and it plays a crucial role in control of autonomic functions [58, 59]. Whether the enhanced activation in PAG explains reversed offset in EDA needs to be determined.

However, whether this EDA response represents a physiological correlate of the OA via pain response is not clear. Indeed, no differences were found for the EDA data within the OT (as is usual for the pain response) when the time intervals T1 and T3 were considered. One can therefore assume that the increased EDA response within T3, may related to an (still) ongoing EDA response caused by a higher stimulation during the T2 interval. Thus, it should be further investigated whether the EDA within an OA paradigm may also reflect the pain predictions that may involve perception of both temperature decreases (OA) and temperature increases (onset hyperalgesia) as shown by Alter et al. 2020 [60].

Our psychological manipulation did not influence the EDA signal. Although EDA has been used extensively to capture reported pain intensity and has been shown to be a potent biomarker in pain prediction [61], we could not observe that autonomic reactivity was influenced by verbal suggestion. Similar results have been reported in some of the previous experiments [62], in which verbal suggestions towards analgesia or hyperalgesia were provided [63]. It cannot be, however, excluded that this is a result of the relatively small effect size observed at the behavioral level (pain).

Psychological mechanisms

The results of this study could serve as an explanatory approach to describe why OA is reduced in chronic pain patients. Various studies showed that a large proportion of chronic pain patients have dysfunctional beliefs about their condition and dysfunctional coping strategies in dealing with their condition [64]. It can be hypothesized that because of these dysfunctional beliefs and coping strategies, chronic pain patients have a fundamentally more negative expectancy toward pain. In this study, a negative expectancy was also evoked in the nocebo group by a suggestion in healthy participants. These participants also subsequently showed reduced OA. Thus, the expectation towards pain could have a decisive influence on the magnitude of OA. For the reduced OA in the nocebo group, the optimism of a person seems to play a role. According to the results, it can be assumed that a more pronounced optimism reduces the effect of suggestion of the nocebo group on OA. Thus, the individual could protect from a more pronounced hyperalgesia as a result of the received suggestion. In contrast, no significance of other psychological factors considered for the effect of the suggestions could be observed.

Conclusion

In this study, suggestion manipulations have been shown to effectively reduce, but not increase, the pain response during OA in healthy participants. Using EDA, this pattern of responses was not observed.

Supporting information

S1 Fig. Schematic representation of the heat stimuli and the suggestion figures of the expected pain perception.

Heat stimuli within the Offset Trial (A): T1 interval (0–9 sec) at 46°C, T2 interval (10–19 sec) at 47°C, T3 interval (20–40 sec) at 46°C. Heat stimuli within the Constant Trial (B): constant at 46°C; suggestion figures of the hypoalgesic group during the Offset Trial (C), pain perception first increases to a level of 50/100, then to 70/100 and drops sharply in the last seconds to an almost non-painful level (approx. 5/100); during the Constant Trial (D), pain perception starts at a level of 50/100 and then slowly and constantly decreases; suggestion images of the hyperalgesic group: during the Offset Trial (E), pain perception first increases to a level of 50/100, then to 70/100 and finally to 50/100 again; during the Constant Trial (F), pain perception remains constant at a level of 50/100.

(PDF)

Click here for additional data file.^{(33.9KB, pdf)}

S1 File. Standardized verbal suggestions.

(DOCX)

Click here for additional data file.^{(16KB, docx)}

S2 File. Additional method of analysis for offset analgesia.

(DOCX)

Click here for additional data file.^{(16KB, docx)}

S3 File. Data set for the analysis.

(XLSX)

Click here for additional data file.^{(542.7KB, xlsx)}

S1 Table. Correlation analysis of pain scores within the third time interval (T3) and included questionnaires.

PHQ9: Patient Health Questionnaire; PVAQ: Pain Vigilance and Awareness Questionnaire; PSQ: Pain Sensitivity Questionnaire; STAIT-SKD: State-Trait-Anxiety-Inventory-SKD; SDS-17: Social Desirability Scale-17; MAAS: Mindful Attention and Awareness Scale, LOT-R: Life-Orientation-Test, r: spearman-correlation coefficient, p: p-value, significant correlations are marked in bold.

(DOCX)

Click here for additional data file.^{(23KB, docx)}

Acknowledgments

The authors thank the Institute of Medical Informatics, University of Lübeck, kindly for providing the research facilities and equipment.

Data Availability

Data is available in the supporting information.

Funding Statement

The study was conducted thanks to support from the National Science Centre in Poland (2020/04/X/HS6/01927). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PONE-D-22-22989Psychological mechanisms of offset analgesia The effect of expectancy manipulationPLOS ONE

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Reviewer #1: “Psychological mechanisms of offset analgesia The effect of expectancy manipulation” is a well-written article describing a fascinating experiment designed to expand the understanding of offset analgesia, which is likely to involve descending inhibition of nociceptive input. Hypothesizing that offset analgesia shares mechanisms with placebo analgesia, they reasoned that one well-known component of placebo analgesia, hypoalgesic suggestion, might amplify offset analgesia. Given the bidirectional nature of descending pain modulation, the investigators also reasoned that hyperalgesic suggestion might attenuate offset analgesia. The study was well executed in a large sample of healthy volunteers. With the currently presented analysis, the hypoalgesic suggestion did not increase offset analgesia compared to control, but instead, a hyperalgesic suggestion decreased offset analgesia. With major changes, this investigation would be a nice addition to the field.

Major issues:

• Data availability – the authors need to specify where the data are and/or provide it for review.

• Reporting pain intensity change as a measure of offset analgesia can be done in several ways, as outlined by the current authors elsewhere (Szikszay et al. Clin J Pain 2018). Statistical testing comparing OT and CT is described in the current analysis. However, within-stimulus subtraction should also be analyzed to determine whether similar effects of suggestion are observed. This is particularly interesting because, from inspecting Fig 2, it seems that if one were to use the within-stimulus measure of offset analgesia used by Niesters et al Anesthesiology 2011 and others ([min – max] / max), the hypoalgesic suggestion may be associated with relatively greater offset analgesia, which would support the investigators’ a priori hypothesis.

• Please provide additional information about the EDA analysis. Is there any signal processing done by the acquiring unit? Is there any preprocessing besides downsampling from 1000 Hz to 1 Hz? How was the downsampling done (program used, method)?

• More should be done in the analysis of the EDA signals. In the control group (N=30), a secondary analysis should be done to determine if there is a significant difference between control and offset stimuli at all timepoints (time series data) and then at timepoints during the T1, T2, and T3 periods. The temporal relationship of the EDA trace to the temperature stimulus should also be highlighted, potentially with markers of the temperature transitions. This analysis would contribute to the field, since this is the first EDA measure during offset analgesia and would support statements in the Discussion about whether EDA reflects a physiological correlate of offset analgesia

• The second increase in EDA (potentially reflecting the transition from 47 to 46 C) may be consistent with offset analgesia when considering that offset analgesia may reflect pain predictions, which themselves may elicit pain increases or decreases during the offset stimulus. As part of the above analysis, it would be interesting to see whether the magnitude of the EDA increase is different with the temperature increase versus decrease (i.e. comparing EDA during T2-T1 versus T3-T2). Along similar lines, the initial increase in EDA may actually relate to a change in pain and not pain intensity per se. Perceptual enhancement of both temperature decreases (offset analgesia) and increases (onset hyperalgesia) has been observed using similar heat stimuli (Alter et al. PLOSOne 2020), so the EDA response may actually be related to pain prediction.

• Is the manipulation placebo or nocebo? There is no administration of an inert compound. The relationship of the described suggestion manipulation to placebo / nocebo effects is highly relevant and interesting, but it would be better to refer to the current manipulation as hypo- or hyperalgesic suggestion, as done in the abstract. Please revise other sections accordingly.

Minor issues:

• Would add a summary paragraph at the end of the Discussion

• Fig 3 – it is unclear which specific comparisons are significant. This is particularly true in the left panel, where it’s hard to tell what the comparison is for the single stars – is this comparing hypo vs hyper and hyper vs control or the OT for each of those conditions? A bracket with descending lines pointing to the specific bars or bar groups might be considered.

• Pg 8 line 156 – would rephrase or move paragraph to the section about the cover story. Rephrasing by stating the purpose of the cover story first would help the flow for the reader.

• P 14 line 275-277 – please rephrase. Ambiguous what “this” is.

• P 15 line 288 – not exclusively a “verbal” manipulation – please rephrase

• P 16 line 310-311 – rephrase last phrase in sentence. Perhaps, “have underlying” instead of “are underlying”

• P 16 line 325 – rephrase “placebo suggestion.” Would delete placebo and stick with terminology in earlier sections.

• P17 line 360 – please rephrase to clarify the different percentages here.

Reviewer #2: I have no concerns about this research. I feel like the manuscript was very well written and only needs minor corrections before publication. The manuscript is also appropriate for the scope and aim of PlosOne.

**********

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Reviewer #1: Yes: Benedict Alter

Reviewer #2: No

**********

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PLoS One. 2023 Jan 17;18(1):e0280579. doi: 10.1371/journal.pone.0280579.r002

Author response to Decision Letter 0

13 Dec 2022

Reviewer #1:

“Psychological mechanisms of offset analgesia The effect of expectancy manipulation” is a well-written article describing a fascinating experiment designed to expand the understanding of offset analgesia, which is likely to involve descending inhibition of nociceptive input. Hypothesizing that offset analgesia shares mechanisms with placebo analgesia, they reasoned that one well-known component of placebo analgesia, hypoalgesic suggestion, might amplify offset analgesia. Given the bidirectional nature of descending pain modulation, the investigators also reasoned that hyperalgesic suggestion might attenuate offset analgesia. The study was well executed in a large sample of healthy volunteers. With the currently presented analysis, the hypoalgesic suggestion did not increase offset analgesia compared to control, but instead, a hyperalgesic suggestion decreased offset analgesia. With major changes, this investigation would be a nice addition to the field.

Response: We would like to thank the reviewer for the valuable time to review our manuscript. We are very pleased with the positive and constructive feedback. We also believe that the proposed and implemented changes have significantly improved the quality of our manuscript.

Major issues:

• Data availability – the authors need to specify where the data are and/or provide it for review.

Response: Thank you for your comment. We would like to attach our dataset as supporting information (please see S4 File). In this way, data will be available without any restrictions.

“The raw data are presented in the supporting information (S4 File).” (p. 11, line 231)

Response: Thank you very much for this comment. We performed the statistical analyses based on the T3 interval of OT and CT, as described in our pre-registration. However, we also agree that an analysis with parameters within the OT are valid. We would therefore like to present the suggested ([min - max] / max) analysis carried out by Niesters et al. (2011), in the supporting information (see S3 File). Interestingly, this analysis does not change the overall conclusions derived from the current study but confirms again that participants in the hyperalgesic group perceived a significantly different offset analgesia effect than the hypoalgesic group and the control group. This strengthens our previous findings. We would like to thank you for this suggestion.

“An additional method of analysis calculating the percentage difference of the maximum pain ratings for T2 and the minimum pain rating for T3 is included in the supporting information (S3 File).” (p. 10, line 213, ff)

“Results for an additional method of analysis are presented in the supporting information (S3 File).” (p. 14, line 276, ff)

Response: Thank you for this comment. We have now included additional information on the EDA analysis in our manuscript. EDA data were measured with a sampling rate of 1000 Hz (PLUX Wireless Biosignals, S.A., Portugal) (please see p. 6, line 125). Downsampling of the time-series data was performed by using the ‘resample’ method of the ‘pandas’ package in Python (Python 3.9.7, pandas 1.4.2). There were no further preprocessing steps.

“The time-series data were down-sampled to a frequency of 1 Hz by using the “resample” function of the python package “Pandas” (Python 3.9.7, pandas 1.4.2). Here, multiple data points are aggregated and replaced by their average. No further preprocessing steps were performed.” (p. 9, line 190, ff)

Response: Thank you very much for this comment. We would like to provide further analyses. However, we would like to propose analyses based not on all time points (time series, each second), but on defined time intervals. For this purpose, we would like to suggest the pain ratings and EDA data of the last 5 seconds of the T1 and T2 interval and the mid 10 seconds of the T3 interval (please see p. 5, line 199 following). As shown in Fig. 2 and 4, this corresponds to a constant value in time for pain and EDA response, respectively, in which the signal does not increase or decrease continuously. Likewise, on the one hand, the extracted time intervals (T1, T2, T3), but also the performed statistical models (general linear model) are thus comparable with other analyses here in the manuscript (as also described in the preregistration). As you suggested, in a secondary analysis, we now analyzed differences between OT and CT of EDA response for T1, T2, and T3. Likewise, we analyzed differences between T1, T2, and T3 within OT for the EDA response. No significant differences were found for T1 between OT and CT, but significant differences were found between T2 and T3. However, no significant differences were found within the OT trial between T1 and T3 but between T1 and T2 and between T2 and T3. We now describe these in the results section (p. 15, line 297 following) and added it to the discussion (p. 20, line 413 following). Furthermore, we have highlighted temperature intervals in Figures 2 and 4.

“Secondary analyses of the EDA data within the control group revealed a significant interaction between the factors “interval” (T1, T2, T3) and “trial” (OT, CT) (F[1.4, 62] = 9.0, p = 0.002, �2p = 0.23). Bonferroni-corrected post-hoc comparisons showed significant differences between OT and CT for the interval T2 (p <0.001) and T3 (p = 0.002), but not for the interval T1 (p = 0.42). Furthermore, within the trial OT significant differences were found between T1 and T2 (p = 0.002) and between T2 and T3 (p < 0.001), but not between T1 and T3 (p = 1.00).” (p. 15, line 297 ff)

Response: Thank you for this comment. We have performed the suggested analysis of the EDA data. The difference between T2 and T1 was not significantly different from the difference between T3 and T2 (p = 0.84). In contrast to the increased EDA signal in T3 of the OT compared to the CT, the lack of difference when T1 and T3 time intervals were considered does not indicate a physiological correlate. We would like to consider this in the discussion. We would also like to point out that for a definitive statement on this, this should be further investigated. For this purpose, the onset hyperalgesia paradigm suggested by you is particularly well suited.

“A dependent t-test showed that the EDA magnitude of the increase from T1 to T2 did not differ from the magnitude of the reduction from T2 to T3 (T[31] = 0.21, p = 0.84, dz = 0.04).” (p. 15, line 303 ff)

“However, whether this EDA response represents a physiological correlate of the OA via pain response is not clear. Indeed, no differences were found for the EDA data within the OT (as is usual for the pain response) when the time intervals T1 and T3 were considered. One can therefore assume that the increased EDA response within T3, may related to an (still) ongoing EDA response caused by a higher stimulation during the T2 interval. Thus, it should be further investigated whether the EDA within an OA paradigm may also reflect the pain predictions that may involve perception of both temperature decreases (OA) and temperature increases (onset hyperalgesia) as shown by Alter et al. 2020 [61].”(p. 20, line 413 ff).

Response: Thank you for this comment. The reviewer is right that no administration of a physical treatment serving as a vehicle for placebo effect seems odd. However, we would like point to the fact that contemporary understanding of placebo effects, i.e., placebo analgesia (hypoalgesia) and nocebo hyperalgesia (in the context of pain) exceeds far beyond the mere administration of the inert treatment. According to Benedetti et al. (2011), a context makes the given procedural maneuvers a placebo (or nocebo) leading to placebo (or nocebo) effects. Furthermore, in the seminal work by Colloca & Miller (2011), authors introduced Peirce’s theory of sign, wherein the mere information seems to be a core to trigger expectations leading eventually to behavioral change (e.g., the placebo effect). Thus, any sort of procedure seems to convey an information, and this is its meaning to patients which provokes the placebo effect. In our study, the information was explicitly verbalized and had a form of verbal suggestion. Furthermore, the reviewer is right that the terms should be used more consistently. We have revised the manuscript and used the terms hypo- or hyperalgesic suggestion consistently.

References:

• Benedetti F. (2006). Placebo analgesia. Neurological sciences: official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 27 Suppl 2, S100–S102. https://doi.org/10.1007/s10072-006-0580-4

• Colloca, L., & Miller, F. G. (2011). How placebo responses are formed: a learning perspective. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 366(1572), 1859–1869. https://doi.org/10.1098/rstb.2010.0398

Minor issues:

• Would add a summary paragraph at the end of the Discussion

Response: We have included a summary at the end of the discussion:

“In this study, suggestion manipulations have been shown to effectively reduce, but not increase, the pain response during OA in healthy participants. Using EDA, this pattern of responses was not observed.” (p. 21, line 446 ff)

Response: You are correct, the original figure with marked comparisons was not straightforward. We have now revised Fig 3. The upper comparisons denote comparisons between the groups of OTs. The lower comparisons indicate differences between OTs and CTs from T3 within each group.

• Pg 8 line 156 – would rephrase or move paragraph to the section about the cover story. Rephrasing by stating the purpose of the cover story first would help the flow for the reader.

Response: Thank you very much for this comment. We would like to describe the cover story prior to the suggestions.

• P 14 line 275-277 – please rephrase. Ambiguous what “this” is.

Response: We have now clarified this:

„Pain response consistent with the provided suggestion (…).” (p. 14, line 291-292)

• P 15 line 288 – not exclusively a “verbal” manipulation – please rephrase

Response: We have adapted this as well.

• P 16 line 310-311 – rephrase last phrase in sentence. Perhaps, “have underlying” instead of “are underlying”

Response: Thank you very much, we have corrected it.

• P 16 line 325 – rephrase “placebo suggestion.” Would delete placebo and stick with terminology in earlier sections.

Response: We have corrected this as well.

• P17 line 360 – please rephrase to clarify the different percentages here.

Response: We have adapted this as follows:

“Although the majority (70.1%) of the subjects reported that they perceived a pain response during OT according to the prior given suggestion. However, in contrast to the hypoalgesic group (90.6%), only 21.2% in the hyperalgesic group confirmed a pain response as suggested.” (p. 18, line 387 ff)

Reviewer #2:

I have no concerns about this research. I feel like the manuscript was very well written and only needs minor corrections before publication. The manuscript is also appropriate for the scope and aim of PlosOne.

Response: Thank you for taking the time to review the manuscript. We are very happy about your positive feedback.

Additional comments

General: The current manuscript looks to examine the psychological mechanisms related to offset analgesia. While many mechanisms have been examined in relation to offset analgesia, the use of psychological interventions is a novel methods determining endogenous pain modulation. This study used suggestions to determine the degree of offset analgesia during two separate trials using an experimental heat stimulus. The study found that offset analgesia was present in all groups, regardless of the type of suggestion provided. While I feel the manuscript is very well written, there are some things that can be added to improve the overall quality.

Response: Once again, thank you for taking the time to review the manuscript. We also appreciate your positive feedback.

COMMENTS

Introduction

Lines 64-71: you introduce the terms placebo and nocebo. You should define these terms for the reader. While placebo is fairly common, nocebo is less so and readers may not understand its intent.

Response: Thank you for this comment. As suggested by Reviewer 1, we would like to avoid using the terms "placebo" and "nocebo" as they can be misleading in this context. Therefore, we have replaced these terms with hypo- or hyperalgesic suggestion in the manuscript.

Methods

Lines 98-103: It would help if you included the suggestions used in this section.

Response: Thank you very much for this comment. We have now clarified this:

“…i) the hypoalgesic group with suggestion towards profound hypoalgesia following the temperature reduction, ii) the hyperalgesic group with verbal suggestion towards hyperalgesia following the temperature reduction …” (p. 5, line 100 ff)

Lines 107-108: How did participants confirm they were otherwise healthy? Did you use a PARQ or some other questionnaire?

Response: Participants were asked whether they would subjectively describe themselves as healthy at this point in time. This was confirmed in writing and verbally by all included subjects. We would like to make this clearer as well:

“All participants had to subjectively confirm that they were healthy”. (p. 6, line 108)

Lines 142-144: Explain in more detail how participants rated their perceived pain. Did they use a touchscreen or did they have a mouse? How often were ratings given?

Response: Thank you for this comment. A computerized visual analogue scale device (COVAS, Medoc, Ramat Yishai, Israel) was used for pain assessment. The COVAS is an additional device which is compatible with the Pathway CHEPS thermal stimulator. The COVAS itself transforms the movement of the slider into digital metric of reported pain. Participants are asked to provide a continuous VAS assessment in real time using this slider. All participants received two offset and two constant trials and were asked to rate pain during each trial. We have now clarified this in the following section:

„A computerized visual analog scale hardware device (COVAS; with the range 0 = "no pain" to 100 = "most tolerable pain") was used for continuous assessment of pain intensity (Medoc, Ramat Yishai, Israel).” (p. 6, line 122 ff)

Results

Line 230: Include a closed parathesis after 0.06 and include a space between that and ‘or’

Response: We apologize for this typo. It has been corrected.

Attachment

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PLoS One. doi: 10.1371/journal.pone.0280579.r003

Decision Letter 1

Kelly Naugle

2 Jan 2023

PONE-D-22-22989R1Psychological mechanisms of offset analgesia: The effect of expectancy manipulationPLOS ONE

Dear Dr. Szikszay,

Please submit your revised manuscript by Feb 16 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

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Kelly Naugle, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

The manuscript has substantially improved with the revisions and only is in need of minor revisions. Specifically, as pointed out by Reviewer 2, it appears that the dataset shared does not include the complete dataset. Also, the timeseries data plotted in Figures 2 and 4 does not appear in the dataset file. Please include a data dictionary for all of the variables.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: The manuscript is substantially improved. Additionally, the letter response provided some excellent discourse which was much appreciated.

The one issue remaining is that the dataset shared does not include the complete dataset. The timeseries data plotted in Fig 2 and Fig 4 is not in the dataset file. Additionally, a data dictionary should be included for all variables. Prior to publication, please confirm supplemental files have the correct number within the file.

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Benedict J Alter

Reviewer #2: No

**********

PLoS One. 2023 Jan 17;18(1):e0280579. doi: 10.1371/journal.pone.0280579.r004

Author response to Decision Letter 1

3 Jan 2023

Journal Requirements:

Response: Thank you for this comment. All cited papers were checked using The Retraction Watch Database. Minor errors were noticed following verification of the accuracy of the reference list. These have been corrected. All changes are marked in yellow.

Additional Editor Comments:

Response: Also thank you for this comment. The dataset has been revised. On the first page of the excel table (S4_File) you now find a clear data dictionary. The characteristics follow on the second page. This is followed by the pain ratings and EDA responses divided by the three groups. We believe that the dataset is now clear and concise.

Reviewer #1:

The manuscript is substantially improved. Additionally, the letter response provided some excellent discourse which was much appreciated.

Response: Thank you again for reviewing our manuscript. We are sure that your suggestions have improved the quality a tremendous amount.

Response: We have revised the dataset. The first page of the Excel spreadsheet (S4_File) now includes a straightforward data dictionary. Following on the second page are the characteristics of the study subjects. Next are the pain ratings and the EDA responses, divided by the three groups (hypoalgesic, hyperalgesic, control). We believe the data set is now clear and concise. We have also corrected the typo in the numbering of the supplemental files.

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PLoS One. doi: 10.1371/journal.pone.0280579.r005

Decision Letter 2

Kelly Naugle

4 Jan 2023

Psychological mechanisms of offset analgesia: The effect of expectancy manipulation

PONE-D-22-22989R2

Dear Dr. Szikszay,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Kelly Naugle, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0280579.r006

Acceptance letter

Kelly Naugle

5 Jan 2023

PONE-D-22-22989R2

Psychological mechanisms of offset analgesia: The effect of expectancy manipulation

Dear Dr. Szikszay:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

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on behalf of

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Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Schematic representation of the heat stimuli and the suggestion figures of the expected pain perception.

(PDF)

Click here for additional data file.^{(33.9KB, pdf)}

S1 File. Standardized verbal suggestions.

(DOCX)

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S2 File. Additional method of analysis for offset analgesia.

(DOCX)

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S3 File. Data set for the analysis.

(XLSX)

Click here for additional data file.^{(542.7KB, xlsx)}

S1 Table. Correlation analysis of pain scores within the third time interval (T3) and included questionnaires.

(DOCX)

Click here for additional data file.^{(23KB, docx)}

Attachment

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Submitted filename: Response to Reviewers.docx

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Attachment

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Data Availability Statement

Data is available in the supporting information.

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PERMALINK

Psychological mechanisms of offset analgesia: The effect of expectancy manipulation

Tibor M Szikszay

Waclaw M Adamczyk

Janina Panskus

Lotte Heimes

Carolin David

Philip Gouverneur

Kerstin Luedtke

Roles

Abstract

Introduction

Materials and methods

Study design

Fig 1. Study design.

Study population

Equipment

Experimental heat stimulation

Suggestion

Questionnaires

Manipulation check

Statistical analysis

Results

Table 1. Participant characteristics for each group.

Fig 2.

Fig 3.

Fig 4.

Discussion

Expectancy mechanism

Physiological mechanisms

Psychological mechanisms

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Kelly Naugle

Roles

Author response to Decision Letter 0

Decision Letter 1

Kelly Naugle

Roles

Author response to Decision Letter 1

Decision Letter 2

Kelly Naugle

Roles

Acceptance letter

Kelly Naugle

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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