Experimental Reduction of Pain Catastrophizing Modulates Pain Report but Not Spinal Nociception As Verified by Mediation Analyses Ellen L

Research Paper

Experimental reduction of pain catastrophizing modulates pain report but not spinal nociception as verified by mediation analyses Ellen L. Terry, Kathryn A. Thompson, Jamie L. Rhudy*

Abstract Pain catastrophizing is associated with enhanced pain; however, the mechanisms by which it modulates pain are poorly understood. Evidence suggests that catastrophizing modulates supraspinal processing of pain but does not modulate spinal nociception (as assessed by nociceptive flexion reflex [NFR]). Unfortunately, most NFR studies have been correlational. To address this, this study experimentally reduced catastrophizing to determine whether it modulates spinal nociception (NFR). Healthy pain- free participants (N 5 113) were randomly assigned to a brief 30-minute catastrophizing reduction manipulation or a control group that received pain education. Before and after manipulations, 2 types of painful stimuli were delivered to elicit (1) NFR (single trains of stimuli) and (2) temporal summation of NFR (3 stimulations at 2 Hz). After each set of stimuli, participants were asked to report their pain intensity and unpleasantness, as well as their situation-specific catastrophizing. Manipulation checks verified that catastrophizing was effectively reduced. Furthermore, pain intensity and unpleasantness to both stimulation types were reduced by the catastrophizing manipulation, effects that were mediated by catastrophizing. Although NFRs were not affected by the catastrophizing manipulation, temporal summation of NFR was reduced. However, this effect was not mediated by catastrophizing. These results indicate that reductions in catastrophizing lead to reductions in pain perception but do not modulate spinal nociception and provides further evidence that catastrophizing modulates pain at the supraspinal, not the spinal, level. Keywords: Pain catastrophizing, RIII reflex, Spinal nociception, Psychophysiology, Pain modulation, Supraspinal processing

1. Introduction have mostly been cross-sectional, examining the associations Pain catastrophizing is associated with a number of adverse between individual differences in pain catastrophizing and short- and long-term pain-related outcomes.29,43 At this time individual differences in NFR. This approach may not be as though, the mechanisms by which catastrophizing influences sensitive to detecting the catastrophizing–NFR relationship as pain are not clearly understood. Evidence from imaging studies would an experimental approach that examines within-subject has shown that catastrophizing is correlated with pain-related changes in pain catastrophizing and NFR. Indeed, within- 18,39 subject comparisons are more statistically powerful than activity in a number of brain regions ; thus, pain catastrophizing seems to modulate pain processing at the supraspinal level. between-subject comparisons. Moreover, an experimental Moreover, catastrophizing is associated with less effective approach allows a stronger inference of the causal relationship descending pain inhibition6,48 and enhanced temporal sum- between the manipulated variable (catastrophizing) and the mation of pain (psychophysical correlate of spinal sensitiza- dependent variable (DV) (spinal nociception). tion),8,17,19,35 which suggests that catastrophizing might To our knowledge, only 4 studies have tried to experimentally engage descending systems to modulate spinal nociception. manipulate catastrophizing to determine its effect on experimental pain processing, and only 1 study examined NFR as an However, several studies have failed to find a relationship 20,31,40,49 between pain catastrophizing and (1) nociceptive flexion outcome. All of these studies attempted to experimen- reflex (NFR) threshold (physiological correlate of spinal noci- tally “increase” catastrophic thinking, and none examined ception)13,14,34,36 and (2) temporal summation of NFR whether experimentally induced changes in catastrophizing ([TS-NFR]; physiological correlate of spinal sensitization).27,35 mediated the observed effects on pain-related outcomes. To These data imply that catastrophizing does not modulate spinal extend this literature, this study experimentally “reduced” catastrophizing and examined the effect on pain intensity/ nociception. However, studies of catastrophizing and NFR unpleasantness and NFR/TS-NFR. The effectiveness of the catastrophizing manipulation was assessed using the Pain Sponsorships or competing interests that may be relevant to content are disclosed Catastrophizing Scale (PCS) with modified instructions to assess at the end of this article. catastrophizing that occurred during pain testing (ie, situation- 5,35 Department of Psychology, The University of Tulsa, Tulsa, OK, USA specific catastrophizing). Mediation analyses were used to *Corresponding author. Address: Department of Psychology, The University of formally test whether a change in catastrophizing was re- Tulsa, 800 South Tucker Drive, Tulsa, OK 74104, USA. Tel.: (918) 631-2839; fax: sponsible for any changes in pain and NFR/TS-NFR that (918) 631-2833. E-mail address: [email protected] (J. L. Rhudy). occurred in response to the experimental manipulation. We PAIN 156 (2015) 1477–1488 predicted that the catastrophizing reduction group would exhibit © 2015 International Association for the Study of Pain lower pain catastrophizing, reduced pain report, and reduced http://dx.doi.org/10.1097/j.pain.0000000000000192 NFR and TS-NFR after the manipulation, relative to the control

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group. But, given the lack of preexisting data, no hypotheses Technologies, West Warwick, RI) was applied. Before the ground were made regarding the mediation analyses. and stimulating electrodes were applied, the skin was cleaned with alcohol and exfoliated using an abrasive paste (Nuprep; Weaver and Company, Aurora, CO) to reduce impedances below 5kV. 2. Materials and methods Electromyographic signals were sampled at 1000 Hz, amplified 2.1. Participants (320,000), and filtered (10 Hz-300 Hz) online using Grass Technologies Model 15LT amplifiers (with AC Module 15A54). The participants were 113 healthy pain-free individuals recruited from The University of Tulsa psychology subject pool and the greater Tulsa community. Subject pool participants received 2.4. Questionnaires research credit, and community participants received a $50 2.4.1. Background variables honorarium. Participants were excluded for the following self- reported conditions: (1) neurological, cardiovascular, or circula- A custom-built demographic and health status questionnaire was tory problems; (2) chronic pain; (3) recent psychological trauma; used to obtain standard background information about the (4) use of over-the-counter pain medication within 24 hours or participants and information regarding health problems. It was prescription pain medication within 2 weeks of participation; (5) administered immediately after informed consent. The question- use of antidepressant, anxiolytic, or high blood pressure naire asked about demographic information such as gender, age, medications; (6) having a body mass index 35 or above (due to race, marital status, years of education, and employment status, difficulty recording a nociceptive reflex because of high adiposity); as well as potential exclusionary criteria such as cardiovascular and (7) being under the age of 18. Although they were not problems, neurological problems, chronic pain, and medication excluded from participation, participants who failed to cata- use. This questionnaire was used to ensure that participants met strophize during pretests were excluded from analyses to inclusion criteria for the study. eliminate problems with floor effects. Participants were given information about the study procedures and provided informed consent before testing. Participants were told that they were free 2.4.2. Pain catastrophizing to discontinue participation at any time during the study. All The PCS is a reliable and valid 13-item questionnaire that procedures were approved by The University of Tulsa Institutional assesses catastrophic thinking associated with pain.44 For this Review Board before data collection. study, the PCS was administered using traditional and situation- specific pain catastrophizing instructions. The traditional instructions inquire about the “degree to which you have these thoughts 2.2. Apparatus and feelings when you are experiencing pain.” The traditional Questionnaire presentation and physiological data collection were PCS was used to assess trait catastrophizing and to see whether controlled by a computer with dual monitor capacity and A/D board results from previous correlational studies could be replicated. (PCI-6071E; National Instruments, Austin, TX). Custom-built Lab- Additionally, instructions to assess situation-specific catastroph- VIEW software (National Instruments) was used to control timing of izing (“Thinking back to your experience during the electric the experimental protocol and all offline data reduction. One stimulations, please indicate the degree to which you had these computer monitor was used by the experimenter to monitor thoughts and feelings”) inquired about the level of pain physiological signals and experimental timing, whereas the second catastrophizing to the painful stimuli used in this study. monitor was used by the participant to complete electronic Measurement of situation-specific pain catastrophizing allowed questionnaires and to make ratings of electric stimuli. Testing us to assess changes in catastrophizing that occurred in was completed in a sound-attenuated and electrically shielded response to the experimental manipulations and to eliminate testing chamber, and participants were monitored from an participants who did not catastrophize during pretests. Impor- adjacent control room through a video camera connected to a flat tantly, previous longitudinal studies using cross-lagged panel panel monitor. Participants wore a pair of sound-attenuating analysis have found that situation-specific catastrophizing is an headphones that allowed them to hear the experimenter. antecedent to pain, not a consequence of it.4,5 This is important Electric stimuli to the sural nerve were generated by a Digitimer for interpreting the effects of situation-specific catastrophizing stimulator (DS7A; Hertfordshire, United Kingdom) and were given that it is measured after the painful stimulus. For both delivered using a bipolar surface-stimulating electrode (Nicolet; versions of catastrophizing, all items were summed to achieve Middleton, WI 30 mm interelectrode distance) attached to the left a total score that ranged from 0 to 52, with higher scores leg over the retromalleolar pathway of the sural nerve. Electric representing more catastrophic thinking. stimuli were delivered in trains of five 1-millisecond pulses at 250 Hz. However, participants experience each train as a single electric pulse/stimulus. To test TS-NFR, 3 stimuli were delivered at 2 Hz 2.4.3. Pain ratings (ie, stimulations were experienced as 3 electric stimuli at 0.5-second Participants were asked to rate their pain intensity and pain intervals). The computer controlled the timing of the stimulations, unpleasantness in response to electrocutaneous stimulations and the maximum stimulation intensity was set at 50 mA. using vertically oriented computer-presented visual analog scales. Anchors for pain intensity were “no pain sensation” and “the most intense pain sensation imaginable,” whereas the anchors for pain 2.3. Electrode application and signal acquisition unpleasantness were “not at all unpleasant” and “the most The NFR was assessed from biceps femoris electromyogram (EMG) unpleasant imaginable.” No numbers were displayed on the scale; recorded from 2 active Ag–AgCl electrodes that were placed 10 cm however, the computer converted the participants’ ratings on the superior to the popliteal fossa. A ground electrode was placed over visual analog scales to scores that ranged from 0 to 100 for each. the lateral epicondyle of the femur. All electrodes were attached To make ratings, participants moved an indicator upwards along with self-adhesive collars after conductive gel (EC60; Grass the scales to indicate their ratings and submitted their answer by

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selecting a “submit” button. The scales returned to zero after between 8 and 12 seconds. Nociceptive flexion reflex magnitude participants submitted their ratings. Participants were instructed was calculated as a d score. To calculate the d score, 4 summary how to discriminate pain intensity and unpleasantness and how to statistics were obtained: (1) mean rectified EMG during the 90- to use the computerized scales before the experiment. 150-millisecond poststimulus interval, (2) SD of rectified EMG during the 90- to 150-millisecond poststimulus interval, (3) mean rectified EMG during the 60-millisecond prestimulus interval, and 2.5. Determination of suprathreshold stimulation intensity (4) SD of rectified EMG during the 60-millisecond prestimulus Before pretests, NFR threshold and 3-stimulus threshold values interval. d 5 (mean of poststimulus interval 2 mean of were assessed to determine the suprathreshold stimulus intensity prestimulus interval)/(average of 2 interval SDs). Research has used during pretests and posttests. Stimulation intensity was set shown that calculating NFR from a d score produces a stronger at 120% NFR threshold or 120% of 3-stimulus threshold, correlation with pain ratings than other methods of scoring NFR whichever was higher. However, the participant was unaware magnitude and improves normality of the NFR distribution.30,33 that only 1 stimulus intensity was used. 2.6.2. Temporal summation of nociceptive flexion reflex 2.5.1. Nociceptive flexion reflex threshold assessment Temporal summation of NFR is a progressive increase in NFR Nociceptive flexion reflex is a spinally mediated nociceptive reflex magnitude after repetitive stimulation of the same intensity.1,28,45 that is used as a marker of spinal nociception but can be dissociated To assess TS-NFR, a block of 5 temporal summation stimuli (ie, 3 from pain perception.37,38 This demonstrates that spinal nocicep- stimulations experienced as 3 stimuli at 2 Hz) were delivered.45 To tion is neither necessary nor sufficient for pain perception and calculate TS-NFR, the average rectified biceps femoris EMG in underscores the importance of assessing both NFR and pain. the first baseline interval (60 milliseconds prestimulus) and the Nociceptive flexion reflex threshold was assessed using 3 average rectified EMG in the NFR intervals (70-150 milliseconds ascending–descending staircases of electric stimulations (a train poststimulus) after each of the 3 stimulations were calculated. of five 1-millisecond pulses at 250 Hz).15,32 The first ascending– Nociceptive flexion reflex d scores for each of the 3 stimulations descending staircase started at 0 mA and increased by 2 mA until were calculated using the equation noted above; however, the an NFR was detected. Nociceptive flexion reflex was defined as a first baseline mean and SD were used for all 3 NFRs. Temporal mean biceps femoris EMG response in the 90- to 150-millisecond summation of nociceptive flexion reflex was defined as the poststimulus interval that exceeds the mean biceps femoris EMG difference of the third NFR minus the first NFR (ie, NFR3 2 NFR1). activity during the 60-millisecond prestimulus baseline interval by Previous research demonstrated that using the 70- to at least 1.4 SDs.32 Using the 90- to 150-millisecond poststimulus 150-millisecond poststimulus interval during TS-NFR testing is interval to define the NFR avoids contamination from non- better than the 90- to 150-millisecond interval because the nociceptive responses, such as startle and voluntary move- latency for NFR onset shortens with repeated stimulations.1 ments.7 After an NFR was obtained, the stimulus intensity was decreased by 1 mA until an NFR was no longer detected. The 2.7. Experimental groups for manipulating catastrophizing second and third ascending–descending staircases also used 1-mA steps. Nociceptive flexion reflex threshold was defined as Participants were randomly assigned to 1 of 2 groups (stratified the average stimulus intensity (in mA) of the 2 peaks and 2 troughs by sex) in order to manipulate pain catastrophizing: pain of the last 2 ascending–descending staircases. The interval catastrophizing reduction group or pain education group. between electric stimulations varied randomly between 8 and 12 seconds to reduce predictability. 2.7.1. Pain catastrophizing reduction group Participants in the pain catastrophizing reduction group first 2.5.2. 3-Stimulus threshold received general education about pain and were provided A single ascending staircase was used to assess 3-stimulus a rationale for the manipulation. Specifically, participants were threshold. The staircase started with a series of 3 electric stimuli educated about the pain pathway, which involved discussing (stimuli 5 five 1-millisecond pulses at 250 Hz) at 2 Hz (0.5-second how pain signals are transmitted to the spinal cord and the brain. interstimulus interval) set at 0 mA. The intensity of the stimulus Participants then learned about problems with the pain pathway series was increased by 1 mA until the third stimulus in the series explanation and were informed about the gate control theory and evoked an NFR according to the definition used in NFR threshold how other processes (eg, endogenous opioids) can influence testing. This procedure was used to ensure reliable reflexes pain experience by opening or closing the gate to regulate pain during TS-NFR testing.45 messages. Next, participants were educated about how negative thoughts or beliefs (eg, I can’t deal with this), negative memories (eg, this reminds me of a pain I’ve had in the past), or negative 2.6. Pain and nociceptive flexion reflex/temporal summation expectations (eg, this pain will get worse) might trigger the gate to of nociceptive flexion reflex assessment open and cause more pain signals to get to the brain. By contrast, After the stimulus intensity was determined, NFRs in response to positive thoughts or beliefs (eg, there are things I can do to control single stimulations and TS-NFR were assessed before and after or cope with this pain) or positive expectations (eg, no matter how the manipulations. bad it gets, I know I can cope with the pain) might trigger the gate to close allowing fewer pain signals to get to the brain. This discussion was the introduction for the use of pain control 2.6.1. Nociceptive flexion reflex in response to single statements. Pain control statements were anticatastrophizing stimulations statements that were based on items from the PCS. Participants To assess NFR, a block of 5 single suprathreshold stimulations were instructed to choose 3 from a list of 26 statements that were were delivered to the ankle with a random interstimulus interval used for the remainder of the study. For example, “this hurts, but I

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have the control,” “I can control my reaction by controlling the way presented in a separate report. This test was always presented I think about this experience,” and “I tell myself to be brave and after NFR, and TS-NFR was assessed at pretest and posttest). carry on despite the pain.” During the last part of the Pain intensity, pain unpleasantness, and situation-specific manipulation, participants were guided through 3 imaginal catastrophizing were assessed immediately after each set of 5 exposure practice exercises, each lasting 2 minutes. Participants single stimulations (NFR) and each set of 5 triple stimulations (TS- were instructed to imagine going through the pain tests while NFR). This was done to ensure that the catastrophizing reduction continuously repeating the pain control statements aloud. Before group could focus on their coping strategies during posttests postmanipulation testing, participants were reminded to apply without being interrupted to make pain ratings. After pretests, the strategies they practiced while they received the electrical each group received their manipulation, followed by posttests stimulations. In particular, participants were told to say the pain that were identical to the pretests, except that participants in the control statements aloud and allow the events to occur without pain catastrophizing reduction group were told to use the coping focusing on them. strategies they learned and to repeat their pain control statements aloud. Once all testing was over, participants were debriefed and provided with course credit or a $50 honorarium. 2.7.2. Pain education group The pain education group received information about pain and pain 2.9. Data analysis processing, emphasizing the neurobiology of pain. For example, participants were educated about the neural process that occurs To determine whether there were group differences in participant when sensory nerves respond to painful stimuli, the sensory characteristics, 1-way analysis of variance (ANOVA) and x2 neurons that are involved in pain processing, and the neural analyses were conducted. All other analyses were conducted pathways from the spinal cord to the brain that are involved in pain using linear mixed models (MIXED procedure, SPSS 20.0) to processing. They were also educated on the distinction between increase statistical power and ensure that cases with missing nociception and pain, and learned about 4 different types of data were not excluded.22 Data were kept in long form, meaning nociceptors (ie, high threshold mechanonociceptors, chemical each participant contributed multiple rows of data for each nociceptors, thermal nociceptors, and polymodal nociceptors). In analysis. For example, each set of NFR testing contained 5 addition, participants learned about different types of sensory pretest stimulations and 5 posttest stimulations (thus, 10 rows of neurons (eg, Ad andCfibers)andtherolethattheyplayinpain data), each set of temporal summation testing contained 5 signaling. Next, participants learned about the neural pathways from pretest triple stimulations and 5 posttest triple stimulations (thus, the spinal cord to the brain (eg, neospinal thalamic, paleospinal 10 rows of data), and each block contained 1 pretest and 1 thalamic, archispinal thalamic tracts). The last portion involved posttest pain rating (thus, 2 rows of data). Keeping the data in discussion of brain areas and the role they play in the pain long form increases denominator degrees of freedom (df) for perception. At no time were participants taught about pain within-subject effects, thus greatly increasing power.22 modulation or the interface of thoughts, feelings, and pain. After Subject ID was used as the grouping variable to designate the completing the education, participants were reminded that the next level 2 units to account for nonindependence of observations phase of pain testing was identical to what occurred during pretests. given that each participant contributed multiple rows of data. Level 1 units were responses to electric stimulations (NFR, pain ratings). The variance–covariance structure of the repeated 2.8. Procedure measurements within each set was modeled using an autocor- All procedures were administered in a single session. Participants relation matrix (AR1). All models included a random intercept to who expressed interest in the study were telephoned and provided allow outcomes to vary across individuals (level 2 units). The a brief overview of the study. If interested, they were given a brief SPSS MIXED procedure uses Satterthwaite estimation for the eligibility screen before a session was scheduled. On arrival at the denominator degrees of freedom (df), which produces noninteger laboratory, participants were provided a thorough description of values that vary from analysis to analysis (even if the number of the experimental procedures before informed consent was observations is the same across analyses). These dfs were obtained. Participants also were given the opportunity to ask rounded to the nearest integer for ease of reporting. questions regarding the study procedures and were informed that Phase (pre vs post) was used as a within-subjects independent their behavior was being monitored by a video camera to ensure variable (IV) and Group (Pain Education vs Catastrophizing compliance with study instructions. Next, a health status Reduction) as a between-subjects IV. Dependent variables were questionnaire and interview was administered to thoroughly assess situation-specific pain catastrophizing, pain intensity ratings, pain inclusion/exclusion criteria. Then, participants were familiarized unpleasantness ratings, NFR magnitude, and TS-NFR. In with the pain rating scales and instrumented with electrodes. addition, a continuous predictor (ie, Stimulation Number) was Participants were tested individually while sitting comfortably in entered that coded for the order in which stimulations occurred a reclining chair with the footrest extended (knee angle approxi- within each set of stimuli. This variable controlled for any mately 160˚). Participants were randomly assigned (stratified by habituation or sensitization effects within pretests or posttests. sex) to the catastrophizing reduction group or the pain education Controlling for habituation/sensitization improves statistical group upon entering the study. power and the validity of the statistical models by explaining this Before pain testing, participants completed the PCS using variance rather than assuming it is error. Significant F-tests were traditional instructions. Next, NFR threshold and the 3-stimulus followed up using Fisher’s least significant difference tests. threshold values were assessed followed by pretests, which In the event of a significant interaction, the simple effect of Phase involved 5 single stimulations to elicit NFR and 5 triple stimulations was examined (ie, the pretest vs posttest comparison for each to elicit TS-NFR. (One additional pain test was assessed before group separately) because this provides insight into the primary and after the manipulations. The test involved the presentation of effect of interest; specifically, whether each group changed over 8 pseudorandomly ordered safe and threat periods that were time as a result of their group’s manipulation. However, if the Phase used to assess threat-enhanced pain/NFR. These data will be simple effect tests did not adequately describe the interaction

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(eg, both groups showed a significant decrease from pretest to 3. Results posttest), the simple effect of Group was also examined (ie, the 3.1. Participant dropouts, exclusions, and final sample Pain Education vs Catastrophizing Reduction comparison for each phase separately) to determine whether the Catastrophizing A flowchart detailing the number of participants screened and Reduction group showed a larger reduction than the Pain selected to participate in this study is shown in Figure 1. In total, Education group. Significance was set at P , 0.05 (2-tailed). 251 individuals contacted the laboratory, but after screening, only In the event that hypotheses were supported (ie, pain-related 113 eligible participants were randomized to the pain education outcomes were reduced in the catastrophizing reduction group), (n 5 57) or catastrophizing reduction groups (n 5 56). Of those mediation analyses were conducted to determine whether randomized to the pain education control group, 3 found the changes in situation-specific pain catastrophizing accounted for stimulations too painful and 2 were unable to achieve an NFR. (mediated) the relationship between the Group 3 Phase interaction Thus, data from 52 participants were available for analyses. Of and the pain-related DV. Mediation analysis followed the 3 steps those randomized to the catastrophizing reduction group, 3 outlined by Baron and Kenny.3 First, the relationship between the found the stimulations too painful and 1 was unable to achieve an Group 3 Phase interaction and the pain-related DV (eg, pain rating, NFR. Furthermore, another participant was excluded for not NFR, TS-NFR) was established from the linear mixed-model following instructions (ie, failed to say their anticatastrophizing ANOVAs described above as part of the primary analyses. This statements aloud). Thus, data from 51 participants were available establishes that there is an IV → DV effect to be mediated. Second, for analyses. Table 1 presents group comparisons on de- the relationship between the covariate (pain catastrophizing) and mographic and other relevant characteristics. As can be seen, the pain-related DV (eg, pain rating, NFR, TS-NFR) was established there were no significant group differences on any variable. by examining correlations between the change in situation-specific Because the groups did not differ on suprathreshold intensity, any catastrophizing (posttest minus pretest) and the change in the group differences in pain outcomes cannot be attributed to this pain-related outcome (posttest minus pretest). This establishes potential confound. that mediation is possible because the DV and the mediator covary. And third, the linear mixed-model ANOVAs were ran again 3.2. Responses to single stimulations entering the change in situation-specific pain catastrophizing as a covariate. If the Group 3 Phase interaction was no longer Figure 2 depicts mean values, SEMs, and significant mean a significant predictor in these models, then complete mediation contrasts for situation-specific pain catastrophizing, pain in- was assumed. Specifically, this means that the relationship tensity, pain unpleasantness, and NFR in response to single between the experimental manipulation and change in the pain- stimuli. related DV is best accounted for by changes in the mediator (catastrophizing). However, the 3 steps suggested by Baron and Kenny3 to establish mediation result in a binary outcome (full 3.2.1. Sample available for single stimulation analyses mediation vs no mediation). It is possible for there to be partial Eight participants were excluded because they scored zero on mediation, meaning that some, but not all, of the relationship situation-specific pain catastrophizing, and 2 trials were elimi- between the manipulation and the change in the pain-related DV is nated because biceps femoris EMG baseline was greater than explained by the change in catastrophizing. To test for partial 10 mV. Thus, data from 95 participants (48 pain education, 47 mediation, the Sobel test was used. This tests whether there is catastrophizing reduction) were used in these analyses. a significant reduction in the relationship between the experimental manipulation and the pain-related DV after controlling for the 3.2.2. Situation-specific pain catastrophizing change in catastrophizing. The Sobel test is a z-test and, if significant, provides evidence for a significant reduction in the The main effects of Phase (F(1,95) 5 40.42, P , 0.001) and IV–DV relationship after the mediator is controlled (ie, partial Group were significant (F(1,95) 5 4.56, P 5 0.04), but these mediation). To conduct the Sobel tests, the same analyses were qualified by a significant Group 3 Phase interaction reported above were run with regression, so that the regression (F(1,95) 5 10.57, P 5 0.002). The simple effects of Phase coefficients could be obtained for use in the Sobel analysis. indicated that both groups showed statistically significant reductions in situation-specific catastrophizing during posttest (Ps , 0.05). However, the simple effects of Group indicated that 2.9.1. Data screening before analyses situation-specific pain catastrophizing scores were lower for the All NFR signals were scored offline, and a trained experimenter catastrophizing reduction group relative to the pain education visually inspected the waveforms. Furthermore, data were exam- group after receiving the manipulation (P , 0.05), but not at ined and excluded from analyses for several reasons: (1) pretest (P 5 0.46), suggesting that manipulation significantly participants were excluded from any analysis where he or she reduced situation-specific pain catastrophizing relative to scored zero on situation-specific pain catastrophizing at pretest control. during a particular pain task (to eliminate floor effects), (2) participants were excluded if they withdrew from the study without 3.2.3. Pain ratings completing any posttest tasks, (3) individual NFRs from a participant were eliminated due to a movement that resulted in biceps femoris For pain intensity, the significant main effect of Phase (F(1,94) 5 EMG baseline greater than 10 mV during NFR testing (resting EMG 37.67, P , 0.001) was qualified by the significant Group 3 Phase is typically 2-5 mV on average), and (4) participants were excluded interaction (F(1,94) 5 13.53, P , 0.001). The simple effects of from TS-NFR analyses if they had less than 2 valid TS-NFR trials at Phase indicated that pain intensity was successfully reduced in both pretest and posttest (invalid 5 too much voluntary muscle the catastrophizing reduction group (P , 0.001), but not in the activity in the EMG as defined by baselines .10 mV in response to pain education group (P 5 0.09). There were no significant group stimulations #2 and #3 in the 3-stimulus train). These exclusion differences in pretest pain intensity ratings (P 5 0.95), but there criteria ensured that participants had valid data for analyses. were significant group differences in posttest pain intensity

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Figure 1. Participant flowchart.

ratings (P 5 0.02). The main effect of Group was not significant 3.3. Responses to temporal summation of nociceptive (F(1,95) 5 1.38, P 5 0.24). flexion reflex stimulations For pain unpleasantness, the significant main effect of Phase Figure 3 depicts mean values, SEMs, and significant mean 5 , (F(1,94) 77.42, P 0.001) was qualified by the significant contrasts for situation-specific pain catastrophizing, pain intensity, 3 5 , Group Phase interaction (F(1,94) 27.76, P 0.001). The pain unpleasantness, and TS-NFR in response to triple stimulations. simple effects of Phase indicated that both groups showed statistically significant reductions in pain unpleasantness ratings from pretest to posttest (Ps , 0.05). However, the reduction was 3.3.1. Sample available for temporal summation of nociceptive flexion reflex analyses greater in the catastrophizing reduction group, because there were significant group differences in posttest pain unpleasant- Eight participants were excluded because they scored zero on ness ratings (P , 0.001) but no significant group differences in situation-specific pain catastrophizing during pretest, and 10 pretest pain unpleasantness ratings (P 5 0.93). The main effect of participants were excluded for having too many invalid TS-NFR Group was not significant (F(1,95) 5 3.53, P 5 0.06). trials (3 pain education, 7 catastrophizing reduction). In addition, 52 trials were eliminated because biceps femoris EMG baseline m 3.2.4. Nociceptive flexion reflex was greater than 10 V. Thus, data from 95 participants (49 pain education, 46 catastrophizing reduction) were used in all The main effect of Phase was significant (F(1,281) 5 24.27, P , analyses of catastrophizing and pain ratings, whereas data from 0.001), indicating that NFRs decreased from pretest to posttest in 87 participants (47 pain education, 40 catastrophizing reduction) both groups. However, the main effect of Group (F(1,95) 5 3.17, were available for analyses of TS-NFR. P 5 0.08) and the Group 3 Phase interaction (F(1,310) 5 0.15, P 5 0.70) were both nonsignificant. Thus, the groups did not 3.3.2. Situation-specific pain catastrophizing differ in spinal nociception during single stimulations. There was a significant main effect of Stimulation Number (B 520.06, P , The significant main effect of Phase (F(1,95) 5 104.23, P , 0.001) 0.001), indicating that NFR magnitudes habituated within each was qualified by the significant Group 3 Phase interaction testing block. (F(1,95) 5 37.79, P , 0.001). The simple effects of Phase

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Table 1 Demographic and other group characteristics. Pain education Catastrophizing reduction Pd N Mean (or %) SD Range N Mean (or %) SD Range Honorarium 0.24 Payment 47 82.5 40 71.4 Research credit 10 17.5 16 28.6 Sex 0.93 Male 32 56.1 30 53.6 Female 25 43.9 26 46.4 Age 57 28.1 10.51 18-57 56 29.5 12.22 18-58 0.54 0.12 Ethnicity 0.66 Non-Latina/Hispanic 54 94.7 54 96.4 Latina/Hispanic 3 5.3 2 3.6 Race 0.09 White 40 70.2 47 85.5 Non-white 17 29.8 8 14.5 Years of education 55 14.8 2.9 10-28 56 15.1 2.3 11-22 0.47 0.11 Marital status 0.69 Married 14 24.6 11 19.6 Not married 43 75.4 45 80.4 Employment status 0.77 Employed 30 52.6 32 57.1 Not employed 27 47.4 24 42.9 Body mass index, kg/m2 57 25.0 4.5 17.4-34.6 56 25.3 4.9 16.5-35.2 0.68 0.06 Systolic blood pressure, mm Hg 57 121.0 15.1 99.5-171.5 56 118.5 13.1 93.5-148.8 0.34 0.18 Diastolic blood pressure, mm Hg 57 78.7 11.1 60.8-118.0 56 75.8 9.9 60.0-99.8 0.14 0.28 PCS-Trait (0-52) 57 13.2 9.0 0-42 56 13.0 9.5 0-39 0.92 0.02 NFR threshold, mA 55 19.7 11.9 3.0-49.2 54 20.6 11.4 2.5-46.0 0.67 0.08 3-stimulus threshold, mA 55 16.8 7.6 2.0-34.0 53 15.5 8.2 2.0-36.0 0.40 0.16 Suprathreshold stimulation, mA 54 25.1 12.2 4.8-50.0 53 26.1 12.2 7.2-50.0 0.68 0.08 PCS, Pain Catastrophizing Scale; NFR, nociceptive flexion reflex.

indicated that both groups showed statistically significant 3.3.4. Temporal summation of nociceptive flexion reflex reductions in situation-specific pain catastrophizing from pretest The significant main effect of Phase (F(1,230) 5 21.24, P , 0.001) to posttest (Ps , 0.05). However, the simple effects of Group was qualified by the significant Group 3 Phase interaction indicated that situation-specific pain catastrophizing scores were (F(1,255) 5 14.83, P , 0.001). The simple effect of Phase lower for the catastrophizing reduction group relative to the pain indicated that TS-NFR was reduced in the catastrophizing education group at posttest (P , 0.001), but not at pretest (P 5 reduction group (P , 0.001), but not in the pain education group 0.15), indicating that manipulation significantly reduced situation- (P 5 0.56). There were no significant group differences at pretest specific pain catastrophizing. The main effect of Group was not (P 5 0.67). There also was a significant main effect of Train significant (F(1,95) 5 0.54, P 5 0.46). Number (B 5 0.04, P 5 0.003), indicating that NFRs sensitized within each testing block. The main effect of Group was not 3.3.3. Pain ratings significant (F(1,85) 5 1.39, P 5 0.24). For pain intensity, the significant main effect of Phase (F(1,95) 5 68.55, P , 0.001) was qualified by the significant Group 3 Phase 3.4. Mediation analyses 5 , interaction (F(1,95) 29.34, P 0.001). The simple effects of Table 2 presents the results of mediation tests. As can be seen, Phase indicated that both groups showed statistically significant change in pain catastrophizing fully mediated the relationship , reductions in pain intensity ratings from pretest to posttest (Ps between the Phase 3 Group interaction and unpleasantness 0.05). However, the simple effects of Group indicated that pain ratings to single stimulations. Furthermore, there was evidence intensity ratings were lower for the catastrophizing reduction for partial mediation of (1) intensity ratings of single stimulations, , group relative to the pain education group at posttest (P 0.001), (2) intensity ratings of TS-NFR stimuli, and (3) unpleasantness 5 but not at pretest (P 0.43). The main effect of Group was not ratings of TS-NFR stimuli. Pain catastrophizing did not mediate 5 5 significant (F(1,95) 0.76, P 0.38). the relationships between the Phase 3 Group interaction and any For pain unpleasantness, the significant main effect of Phase of the NFR-related outcomes (NFR magnitudes to single 5 , 3 (F(1,95) 97.52, P 0.001) was qualified by the significant Group stimulations and TS-NFR). Phase interaction (F(1,95) 5 39.19, P , 0.001). The simple effects of Phase indicated that both groups showed statistically significant reductions in pain unpleasantness ratings from pretest to posttest 3.5. Correlation analyses to confirm results of previous research (Ps , 0.05). However, the simple effects of Group indicated that pain unpleasantness ratings were lower for the catastrophizing To assess whether findings from previous correlational research reduction group relative to the pain education group at posttest could be replicated,13,14,27,34–36 correlations were conducted to (P 5 0.001), but not at pretest (P 5 0.39). The main effect of Group determine whether trait and situation-specific pain catastrophiz- was not significant (F(1,95) 5 2.01, P 5 0.16). ing were associated with NFR threshold, NFR magnitude in

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Figure 2. Situation-specific pain catastrophizing, pain intensity, pain unpleasantness, and NFR in reaction to single stimulations. *P , 0.05. SS Pain Catas Ratings 5 situation-specific pain catastrophizing; NFR, nociceptive flexion reflex.

response to single stimulations, and TS-NFR at “pretest only.” and spinal nociception (NFR, TS-NFR). Results indicated the Trait catastrophizing was not associated with any of the NFR- manipulation was successful. Situation-specific pain catastroph- related outcomes: (1) NFR threshold (r 520.19, p 5 0.08), (2) izing was reduced in the experimental group relative to the control NFR magnitudes to single stimulations (r 520.01, P 5 0.90), and group. Importantly, there were no group differences at pretest, (3) TS-NFR (r 5 0.19, P 5 0.31). Similarly, situation-specific pain suggesting that any observed changes in catastrophizing were catastrophizing was not associated with any of the NFR-related not due to differences in initial levels. outcomes: (1) NFR threshold (r 520.004, P 5 0.97), (2) NFR magnitudes to single stimulations (r 5 0.01, P 5 0.92), and (3) 4.1. Pain report TS-NFR (r 520.16, P 5 0.13). The magnitude of correlations between trait catastrophizing Pain intensity and unpleasantness were significantly reduced by and situation-specific catastrophizing was similar to previously the catastrophizing reduction manipulation, relative to the control reported research (situation-specific catastrophizing to single group, across both testing paradigms (NFR, TS-NFR). This is stimulations: r 5 0.41, P , 0.001; situation-specific catastroph- consistent with numerous studies showing that catastrophizing is izing to TS-NFR stimuli: r 5 0.39, P , 0.001).35 associated with pain facilitation16,43,44 and extends this work to demonstrate that experimental reduction of catastrophizing leads to pain reduction. Furthermore, the reduction in pain intensity and 4. Discussion unpleasantness was partially mediated by the reduction in This study examined whether experimental reductions in catastrophizing. This supports previous research indicating that catastrophic thinking could lead to reductions in pain report situation-specific catastrophizing may promote pain facilitation.4,5

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Figure 3. Situation-specific pain catastrophizing, pain intensity, pain unpleasantness, and NFR in reaction to triple stimulations. *P , 0.05. SS Pain Catas Ratings 5 situation-specific pain catastrophizing; NFR, nociceptive flexion reflex; TS-NFR, temporal summation of NFR.

To our knowledge, only 4 studies have attempted to affective–motivational reactions than on pain sensation, which experimentally manipulate catastrophizing.20,31,40,49 Roditi is important given that the affective component of pain contrib- et al.49 found that if chronic facial pain patients engaged in utes to suffering and motivates pain-related behaviors.11 catastrophic statements during a cold-pressor task, they experience greater pain report. Similarly, Ruscheweyh et al.31 4.2. Spinal nociception found that if healthy participants repeated catastrophic statements during electric stimulations, they also experienced greater Interestingly, the catastrophizing reduction manipulation did not pain report (and NFRs, but not TS-NFR). By contrast, the other reduce NFRs in response to single stimulations. This finding was 2 studies had difficulties with their experimental manipula- unexpected because Ruscheweyh et al.31 found that cata- tions20,40; therefore, they observed no change in pain report. strophic statements increased NFRs to single stimulations. This study extended these to demonstrate that changes in pain However, our catastrophizing reduction manipulation did reduce catastrophizing mediate the changes in pain report. TS-NFR. Given that TS-NFR is a measure of spinal sensitization,2 This study also demonstrates that catastrophizing has a larger this might suggest that reducing catastrophizing reduces effect on pain unpleasantness. Specifically, Cohen’s d effect nociceptive amplification at the spinal level. However, catastroph- sizes were larger for the change in unpleasantness ratings (single izing did not mediate this effect; therefore, some other un- stimulations: dintensity 5 0.68 vs dunpleasantness 5 1.11; TS-NFR measured variable must explain this. For example, this study did stimulations: dintensity 5 0.86 vs dunpleasantness 5 1.19). not involve a control group that repeated neutral statements, so This suggests that catastrophizing has a larger effect on we are unable to rule out attentional mechanisms. This should be

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Table 2 Results of mediation analyses. DVs Phase 3 group Phase 3 group Sobel test Conclusion (without mediator) (with mediator) F P F Pz P NFR magnitude (single stimulations) No mediation possible: IV and DV unrelated No mediation Intensity ratings (single stimulations) 13.00 ,0.01 5.57 0.02 22.48 0.01 Partial mediation Unpleasant ratings (single stimulations) 26.97 ,0.01 14.70 0.14 22.70 0.01 Full mediation TS-NFR 9.91 ,0.01 5.23 0.03 20.58 0.56 No mediation Intensity ratings (3 stimulations) 28.72 ,0.01 4.33 0.05 24.31 ,0.01 Partial mediation Unpleasant ratings (3 stimulations) 38.37 ,0.01 7.28 0.01 24.62 ,0.01 Partial mediation This table depicts F-ratio, P-values, and effect sizes for the relationships between the IV (Phase 3 Group interaction) and DV (pain outcomes), with and without the inclusion of the mediator (pain catastrophizing 5 posttest 2 pretest). DV, dependent variable; NFR, nociceptive flexion reflex; IV, independent variable; TS-NFR, temporal summation of NFR.

considered in future research because it would be important to treatment. It is well established that pain catastrophizing has understand what factors can reduce spinal amplification of pain a negative impact on pain and other pain-related domains (eg, signals. physical, psychological, social).29,43 Although previous research Although Ruscheweyh et al.31 found that NFRs were increased has demonstrated that longer multisession interventions to by catastrophic statements, they reported that the participants’ reduce catastrophizing can also reduce pain,23,25,26,47 this study ratings of change in catastrophizing were unrelated to the indicates that even a single 30-minute session can successfully changes in NFR. This suggests that their results are consistent reduce catastrophizing and pain. This is a cost-effective tool and with ours; specifically, changes in catastrophic thinking do not can be easily applied to existing protocols within different mediate the change in spinal nociception. therapeutic settings (eg, clinics, hospitals). Third, reducing catastrophizing may be effective in reducing pain perception,23,25,26,47 but to reduce spinal nociception, 4.3. Differential modulation of temporal summation of treatments may need to include other strategies. For example, nociceptive flexion reflex vs nociceptive flexion reflex evidence suggests that relaxation, a commonly used technique in Temporal summation of nociceptive flexion reflex, but not NFR in cognitive–behavioral therapy, can activate descending mecha- response to single stimulations, was reduced by the catastroph- nisms to inhibit spinal nociception (ie, increase NFR izing reduction manipulation. The reason for the divergence in the 2 threshold).9,10 outcomes was likely due to differences in the physiological Fourth, catastrophizing has a stronger relationship with pain mechanisms that mediate them. Temporal summation of noci- unpleasantness than pain intensity. This supports the notion that ceptive flexion reflex has been shown to be dependent on catastrophizing influences the perception of pain by altering N-methyl-D-aspartate (NMDA) receptors because NMDA antago- supraspinal regions involved with affective–motivational circuitry. nists (eg, ketamine) inhibit TS-NFR.2,21 In contrast, NFRs to single Given that pain unpleasantness is what makes pain seem stimulations are minimally affected (or unaffected) by NMDA unbearable,11,46 interventions that reduce catastrophizing have receptor antagonists.2,41 Rather, evidence suggests that dorsal the potential to significantly reduce pain-related suffering. horn responses to single stimulations are primarily mediated by Fifth, the catastrophizing reduction manipulation reduced TS- a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate NFR, but not by reducing catastrophizing. Thus, there is some (AMPA) receptors.2,12,41 Therefore, the differential modulation of other active ingredient in the manipulation that led to changes in NFR during single stimulations vs TS-NFR might be due to the TS-NFR. Although it is not clear at this time what it is, given that difference in AMPA vs NMDA receptor activation, respectively. pain unpleasantness and TS-NFR are both C-fiber-mediated responses, it is possible that the C-fiber pathway may provide some clues into the mechanism. 4.4. Implications First, given that pain report, but not NFR, was modulated by 4.5. Strengths and limitations a reduction in pain catastrophizing, catastrophizing is likely to facilitate pain perception by modulating signals at the supra- This study had several strengths. First, it is the first study to have spinal, not spinal, level. Several functional magnetic resonance experimentally reduced catastrophizing to determine whether imaging studies have shown that pain catastrophizing was measures of spinal nociception (ie, NFR, TS-NFR) were associated with enhanced pain-related brain activity in areas influenced. Second, this study assessed both pain intensity and such as the anterior cingulate cortex and amygdala,18,39,42 unpleasantness and 2 different correlates of spinal nociception. regions known to influence the emotional aspect of pain Third, formal mediation analyses were conducted to test whether experience. This is in line with the stronger catastrophizing catastrophizing mediated the changes in pain outcomes. And effects on pain unpleasantness noted in this study. Therefore, fourth, a validated catastrophizing measure was used to ensure pain catastrophizing does not seem to engage descending that the manipulation was successful. pathways to modulate spinal nociception but amplifies the pain Despite these strengths, a few limitations should also be noted. experience at the supraspinal level. This conclusion is consistent First, the ability to assess pain might have been affected by with previous correlational studies examining the relationship retrospective pain ratings. Indeed, retrospective ratings can be between catastrophizing and NFR.13,14,27,34–36 affected by report bias and memorial effects.24 However, this Second, this study provides evidence for the therapeutic approach was necessary so that participants in the catastroph- benefits of reducing pain catastrophizing as part of pain izing reduction manipulation group could fully focus on their

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