Delacoba 2018

Psychosomatic Medicine
Author’s Accepted Manuscript
Article Title: Slowly Repeated Evoked Pain (SREP) as a

Marker of Central Sensitization in Fibromyalgia: Diagnostic
Accuracy and Reliability in Comparison With Temporal
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Summation of Pain
Authors: Pablo de la Coba, Stephen Bruehl, Carmen M.

Galvez-Sánchez, and Gustavo A. Reyes del Paso
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DOI: 10.1097/PSY.0000000000000599
Received Date: Nov. 7, 2017

Revised Date: Feb. 14, 2018
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Psychosomatic Medicine Publish Ahead of Print
DOI: 10.1097/PSY.0000000000000599
SLOWLY REPEATED EVOKED PAIN (SREP) AS A MARKER OF
CENTRAL SENSITIZATION IN FIBROMYALGIA: DIAGNOSTIC
ACCURACY AND RELIABILITY IN COMPARISON WITH TEMPORAL
SUMMATION OF PAIN
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Pablo de la Coba1, Stephen Bruehl2, Carmen María Gálvez-Sánchez1, and
Gustavo A. Reyes del Paso1
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Department of Psychology, University of Jaén, Spain
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Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee,
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USA
Address of the corresponding author: Pablo de la Coba. Departamento de Psicología.
Universidad de Jaén. 23071 Jaén, Spain. E-mail: pcoba@ujaen.es Fax: +34953211881.

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Funding sources: This research was supported by a grant from the Spanish Ministry of
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Economy and Competitiveness, co-financed by FEDER funds (Project PSI2015-69235-P), and
two FPU predoctoral contracts (refs: FPU2013-03630 and FPU2014-02808) from the Spanish
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Ministry of Education, Culture and Sport.
Conflict of interest statement
None of the authors have any conflict of interests regarding the study.
Abbreviated running head: SREP as a marker of central sensitization
ABSTRACT
Objective: This study examined the diagnostic accuracy and test-retest reliability of a
novel dynamic evoked pain protocol (slowly repeated evoked pain; SREP) compared to temporal
summation of pain (TSP), a standard index of central sensitization. Methods: Thirty-five
fibromyalgia (FM) and 30 rheumatoid arthritis (RA) patients completed, in pseudorandomized
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order, a standard mechanical TSP protocol (10 stimuli of 1s duration at the thenar eminence
using a 300g monofilament with 1s interstimulus interval) and the SREP protocol (9
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suprathreshold pressure stimuli of 5s duration applied to the fingernail with a 30s interstimulus
interval). In order to evaluate reliability for both protocols, they were repeated in a second
session 4-7 days later. Results: Evidence for significant pain sensitization over trials (increasing
pain intensity ratings) was observed for SREP in FM (p<.001) but not in RA (p=.35), whereas
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significant sensitization was observed in both diagnostic groups for the TSP protocol (p‟s<.008).
Compared to TSP, SREP demonstrated higher overall diagnostic accuracy (87.7% vs. 64.6%),
greater sensitivity (0.89 vs. 0.57), and greater specificity (0.87 vs. 0.73) in discriminating
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between FM and RA patients. Test-retest reliability of SREP sensitization was good in FM
(ICCs: 0.80), and moderate in RA (ICC: 0.68). Conclusions: SREP seems to be a dynamic
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evoked pain index tapping into pain sensitization that allows for greater diagnostic accuracy in
identifying FM patients compared to a standard TSP protocol. Further research is needed to

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study mechanisms underlying SREP and the potential utility of adding SREP to standard pain
evaluation protocols.
KEYWORDS: Fibromyalgia, Central Sensitization, Temporal Summation of Pain, Pain
Threshold, Diagnostic Accuracy, Test-Retest Reliability.
LIST OF ABBREVIATIONS
ACR = American College of Rheumatology
ARA = American Rheumatology Association
CSQ = Coping Strategies Questionnaire
FM = Fibromyalgia
HADS = Hospital Anxiety and Depression Scale
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ICC = Intra-class Correlation
MPQ = McGill Pain Questionnaire
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NRS = Numeric Rating Scale
QST = Quantitative Sensory Testing
RA = Rheumatoid Arthritis
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SD = Standard Deviation
SREP = Slowly Repeated Evoked Pain
TSP = Temporal Summation of Pain
VAS = Visual Analogue Scale

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INTRODUCTION
Fibromyalgia (FM) is a chronic, widespread, and diffuse chronic pain condition whose
etiology remains unknown. However, its pathophysiology seems to be related to central pain
sensitization, involving both brain and spinal mechanisms (1). Greater brain activations in
response to pain-related upregulation of ascending facilitation pathways (2-4), and deficits in
descending spinal inhibitory influences have been found in FM (5-7).
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Typical FM symptoms such as allodynia or hyperalgesia can be explained by this central
pain sensitization.
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Several studies have tried to identify clinical and evoked pain measures to facilitate and
complement FM diagnosis (8-9). Evoked pain indices can be broadly classified into static and
dynamic measures. Static measures evaluate the response to individual painful stimuli under
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basal state conditions of the nociceptive system, whereas dynamic indices reflect pain
responsiveness during repetitive stimulus conditions designed specifically to assess ascending
pain facilatory or descending pain inhibitory pathways (10-12). Pain threshold and tolerance are
the most commonly used static evoked pain measures, which have shown lower values in FM
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patients than healthy individuals (8,13-15). Dynamic measures such as conditioned pain
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modulation (16-18) and temporal summation of pain (TSP) (19-21) have also been examined in
FM, with these measures reflecting descending inhibition and central sensitization, respectively.
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Given that enhanced central pain processing is one of the key pathophysiological factors in FM,
dynamic pain indices may be more useful than static measures to characterize altered pain
processing in FM. Indices based on TSP are potential markers of enhanced central sensitization
in FM (22-23). However, although reliability of TSP seems to be acceptable (24-25), its
diagnostic accuracy in FM may not be optimal, since a significant proportion of FM patients do
not show TSP (26), and TSP can also be observed in other pain conditions or in healthy
individuals (20,27-30).
Recently, we reported a novel dynamic evoked pain protocol called Slowly Repeated
Evoked Pain (SREP), consisting of a single series of 9 supra-threshold painful pressure stimuli
delivered with stimulus duration of 5 seconds and an inter-stimulus interval of 30 seconds (31).
An increasing pain response over time with the SREP protocol (enhanced sensitization) was
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found in FM but not in healthy individuals. Furthermore, SREP differentiated between FM
patients and healthy individuals with an accuracy of 85.4%, greater than that of pain threshold
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and tolerance jointly (72.9%) (31). It should be noted that the SREP protocol differs from TSP in
an important way, specifically, TSP requires repeated pain stimulation at much higher frequency
rates (19-21) than SREP (more than 0.33 Hz versus 0.03 Hz, respectively) (31). Although some
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reports suggest the possibility of observing TSP at stimulus frequencies somewhat lower than
0.33 Hz (22,32), the stimulus frequency in the SREP protocol is substantially lower than in prior
published TSP protocols. The underlying mechanisms of TSP are known to be related to central
sensitization, specifically wind-up processes due to increased activity of dorsal horn neurons (19-
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21). However, the specific mechanisms underlying SREP sensitization (central vs. peripheral)
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remain unknown. Regarding predictive validity, the SREP measure seems to be more strongly
associated with clinical FM pain (r = 0.68) (31) than has been reported for TSP protocols (e.g., r
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= 0.48) (33). Thus, although TSP and SREP share some methodological aspects (the use of
repeated painful stimulation to generate pain sensitization), both methods could show different
diagnostic properties. To date, SREP and TSP protocols have not been directly compared, and
additional research to characterize the SREP protocol appears justified.
In the current study, diagnostic accuracy and test-retest reliability (inter-session stability)
of the SREP protocol in FM patients were analyzed. To better evaluate the discriminative
validity of the SREP protocol as a potential central sensitization marker in FM, the selected
control group was patients suffering from Rheumatoid Arthritis (RA). The rationale for including
this control group was to compare a chronic pain condition mainly related to central pain
sensitization processes (FM) with another chronic pain condition more related to peripheral pain
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sensitization (RA). The RA comparison group was therefore chosen to provide an opportunity to
help clarify the underlying mechanisms (central vs. peripheral) involved in SREP sensitization.
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The study did not include a healthy control group given the previously observed absence of
SREP sensitization in healthy individuals in our prior work (31).
To further validate the SREP protocol, in addition to assessing pain threshold and
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tolerance, TSP was also measured to allow for a direct comparison with SREP sensitization. We
hypothesized that if SREP sensitization were mediated by central mechanisms, significantly
greater SREP sensitization and TSP would be observed in FM relative to RA based on the
different pain mechanisms across the two conditions.

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The aims of the study were: (1) To compare SREP sensitization with a standard TSP
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dynamic evoked pain protocol in FM and RA patients; (2) To examine the diagnostic accuracy
of the SREP protocol in comparison with the TSP protocol regarding ability to differentiate
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between FM and RA patients; (3) To assess and compare the test-retest reliability of SREP and
TSP protocols in FM patients.
MATERIAL AND METHODS
Participants
Thirty-five women suffering from FM and 30 women suffering from RA, matched in age and
body mass index, participated in the study. Diagnosis by a rheumatologist insured that
participants met the 1990 American College Rheumatology (ACR) criteria for FM (34), or 1987
American Rheumatology Association (ARA) criteria for RA (35). All participants were recruited
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from the Fibromyalgia and Rheumatoid Arthritis Associations of Jaén (Spain). Exclusion criteria
for both groups were: presence of cardiovascular disease, metabolic abnormality, hormonal
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disorders, neurological disorder, other diagnosed chronic pain conditions, or severe somatic (e.g.,
cancer) or psychiatric (e.g., psychotic) diseases. Demographic and clinical data are displayed in
Table 1.
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Dynamic evoked pain protocols
To evoke TSP, a mechanical temporal summation protocol was used employing a nylon
monofilament (Touchtest Sensory Evaluator 6.65) calibrated to bend at 300 grams of pressure.
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This technique has been used successfully in previous work to elicit TSP, with responses to this
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mechanical TSP protocol more predictive of clinical arthritic pain than standard thermal TSP
protocols (29). Each mechanical stimulus was applied to the thenar eminence of the left hand at a
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rate of 1 stimulus per second (1 Hz). Two TSP series comprised of 10 mechanical stimuli were
conducted, with an interval of 30s between each series of repeated stimuli. To assess TSP over
repeated stimuli, the subjective pain intensity of each stimulus was assessed via verbal response
using a 0-10 Numeric Rating Scale (NRS), with “0” being “No Pain” and “10” being “Extremely
Painful.”
To generate SREP sensitization (31), a wireless pressure algometer Tracker Freedom
(JTECH Medical, Lawndale, USA), with a surface stimulation area of 1 cm 2 was applied to the
third fingernail of the left hand. The SREP series consisted of 9 supra-threshold painful pressure
stimuli 5 seconds in duration with an inter-stimulus interval of 30 seconds. To assess subjective
pain intensity, a 10 cm visual analogue scale (VAS) was completed following each stimulus,
with the anchors being “No Pain” and “Extremely Painful.”
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The difference in pain assessment formats between the TSP and SREP protocols was
necessitated by the different rates at which pain stimuli were presented in each. The standard
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TSP protocol uses a verbal NRS response format because of the need for rapid assessment
following each pain stimulus (in our case, 1 pain rating/second). The SREP protocol is much
slower and allows for the use of a written VAS (1 pain rating/30 seconds). For consistency with
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our originally published SREP protocol, we elected to maintain the VAS to assess the SREP pain
stimuli, while using the required NRS format for pain assessment in the TSP protocol. To
minimize any potential confounding influence of the different pain assessment formats and to
insure that responses to both were as similar as possible, each participant received instructions
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and training in use of both NRS and VAS ratings prior to the primary study procedures.
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Assessment of clinical and psychological factors

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Levels of clinical pain, catastrophizing, anxiety, and depression were evaluated to analyze
possible confounding influences of these clinical-psychological factors. Clinical pain was
assessed using the Spanish version the McGill Pain Questionnaire (MPQ) with a Cronbach´s
alpha between 0.66-0.80 (36). The MPQ Total score was the index used for quantifying the level
of clinical pain in the current study. Participants also completed the Spanish versions of the
Catastrophizing subscale of the Coping Strategies Questionnaire (CSQ), which has shown
adequate reliability (α = 0.89) (37); and the Hospital Anxiety and Depression Scale (HADS),
which is designed to assess anxiety and depression in medical samples (α = 0.86 for both the
Anxiety and Depression subscales) (38).
Procedure
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The test-retest procedure consisted of two sessions that took place with a between-session
interval from 4 to 7 days (see additional details in Table 1). All participants were asked not to
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consume any analgesic drugs, alcohol, or caffeine, and not engage in physical exercise for 24
hours before each session. The study protocol was approved by the Ethics Committee of the
University of Jaén.
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In the first session (test), a research assistant (other than the experimenter) evaluated
inclusion-exclusion criteria, obtained informed consent and the patient´s clinical history
(including regular medication use), and administered the clinical-psychological measures.
Afterward, evoked pain indices were assessed in two blocks (TSP and SREP blocks). In order to
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limit possible block order effects, TSP and SREP blocks were doubly counterbalanced (both
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within-participants and between sessions).
In the TSP block, TSP was evoked using the procedures described above to generate two
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TSP series. Prior to the actual TSP evaluation and in the first session only, instructions were
provided on the TSP pain rating procedures, including practice in the use of the NRS to rate a
brief test series of 3 stimuli on the right hand. This practice was designed to familiarize patients
with the TSP pain rating procedures and insure that they were able to provide responses at a rate
of 1 verbal pain rating per second during the actual TSP protocol. Five minutes after completing
the actual TSP protocol, the SREP block took place (or vice versa per randomization). Prior to
administering the SREP protocol, pressure algometry on the third finger nail of the left hand was
used to obtain pain threshold and tolerance (31). Instructions regarding the concepts of pain
threshold and tolerance (“first start to feel pain” or “maximum pain stimulation that can be
tolerated”, respectively) were provided to participants. VAS assessment of evoked pain was also
practiced before the pressure pain protocol using a series of three stimuli of different intensities
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(1.5, 2.5, and 2.0 Kg/cm2) on the second finger nail of the left hand. After this practice, pain
threshold and tolerance were determined by applying an increase in pressure at a rate of 1 kg/s
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on the third finger nail of the left hand. Three assessment trials each for pain threshold and pain
tolerance were conducted. Averages of the three measurements were used for determining
pressure intensity during the SREP procedure. This pressure was calculated individually for each
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participant to elicit a calibrated low-to-moderate pain stimulation using the formula: SREP
Intensity = Threshold + 1.25*(DF/4); where DF = Tolerance–Threshold (39). Ten minutes after
the measure of pain threshold and tolerance, a series of nine trials were presented using the same
finger nail. Each pain stimulus involved 5s of constant pressure. Five seconds after removal of
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each pain stimulus in the series, a VAS rating was obtained. Inter-stimulus interval was 30s.
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The second session (retest) consisted of a repetition of the two previously described
blocks to evaluate TSP, pain threshold/tolerance, and SREP sensitization. Clinical pain intensity
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levels (McGill Total score) were also measured in this retest session.
Derivation of SREP & TSP indices
The SREP sensitization index was derived as the difference in pain intensity ratings between the
9th and the 1st SREP trials (31). For the TSP index, the TSP of each one of the two TSP series
was individually derived as the difference in pain intensity ratings between the 10th and the 1st
mechanical stimulus. Then, in order to increase reliability, the average of these two TSP series
was calculated as the final TSP index. For both SREP and TSP, larger positive values indicated
greater pain sensitization.
Statistical analysis
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Kolmogorov–Smirnov and Levene tests showed no deviation from normality or
homogeneity in any of the measured variables (p‟s >.05). Group mean comparisons on threshold,
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tolerance, and derived SREP and TSP measures were conducted with Student´s t-test. Patterns of
pain ratings over trials were analyzed through repeated measures ANOVAs, with one between-
subjects factor (FM vs. RA) and one repeated-measures factor (9 ratings for SREP and 10 ratings
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for TSP). In order to control for differences in clinical pain, total MPQ scores was included as a
covariate in primary analyses. To address the possible impact of individual differences in
participants´ baseline pain sensitivity on TSP results, parallel follow-up analyses included the
first subjective pain rating of each TSP series as a covariate.

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The Greenhouse-Geisser correction was used for possible violations of sphericity

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assumptions. Results are reported with the original degrees of freedom and the corrected p
values. Logistic regression analyses were conducted to test the ability of SREP and TSP to
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discriminate between FM and RA patients. Sensitivity and specificity were derived from the
resulting actual versus predicted group memberships (diagnostic accuracy analyses). Intraclass
correlations (ICCs), as measures of similarity and true agreement (40-41), were computed to
serve as test-retest reliability coefficients for each evoked pain indexes. Associations between
pain measures were assessed using Pearson´s correlations. Differences between correlation
coefficients were tested for significance through Fisher´s Z statistic.
To rule out potential confounds related to psychological factors and regular medication
use on TSP and SREP, we re-ran primary analyses with the psychological variables
(catastrophizing, anxiety and depression) and medication use (patients taking or not taking
antidepressants, anxiolytics, analgesic/opiate drugs) included as covariates. These analyses failed
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to reveal any significant confounding effects of psychological factors or medication use on
evoked pain measures (all p’s > 0.21). Finally, in order to examine possible differences in
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clinical pain across the test-retest sessions, Student´s t-tests for related samples were performed.
No significant differences between test and retest sessions were observed for either group (t = -
0.18, p = 0.86 for FM; t = -0.42, p = 0.68 for RA).

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RESULTS
Table 1 displays means and standard deviations (SD) for demographics, clinical-
psychological measures, and evoked pain indices across groups. There were no group differences
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in demographics or analgesic/opiate use. However, levels of clinical pain, catastrophizing,

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anxiety, depression, and antidepressant/anxiolytic use were higher in FM than RA patients.
There were no group differences in pain tolerance or the averaged pressure used in the SREP
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protocol. However, pain threshold was lower in FM than RA patients and dynamic measures
(TSP and SREP) were greater in FM than in RA patients.
Pain Ratings during TSP versus SREP
As can be observed in Figure 1a, across the ten TSP stimuli, ratings of pain intensity
increased (main effect of trials: F(9,558) = 17.14; p < .001, η2 = .217). However, this increase
differed as a function of group (group × trial interaction: F(9,558) = 7.34; p < .001, η2 = .106).
Simple effects analyses by group showed that the increase in pain ratings was greater in FM
(F(9,297) = 12.71, p < .001, η2 = .278) than in RA patients (F(9,252) = 4.39, p = .008, η2 = .135).
Greater overall subjective pain intensity was observed in FM than RA patients (Group effect:
F(1,62) = 38.75, p < .001, η2 = .385). The effects of clinical pain as a covariate did not reached
significance (F(9,558) = 0.84; p = .474, η2 = .217). Parallel analyses including the first
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subjective pain rating of the TSP series as a covariate showed that both the main effect of trials
and the group × trial interaction remained significant (all p’s < .001). The effect of this covariate
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(first subjective pain rating; (F(9,549) = 0.85; p = .470, η2 = .059) and the main effect of group
(in overall pain intensity ratings; (F(1,61) = 3.42, p = .069, η2 = .385) did not reach
significance.
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Across the nine SREP stimuli, pain intensity significantly increased (F(8,496) = 18.26; p
< .001, η2 = .228), and this also differed as a function of group (F(8,496) = 30.97; p < .001, η2 =
.333). While pain ratings increased progressively in FM (F(8,208) = 21.76, p < .001, η2 = .397),
no change was observed in RA (F(8,224) = 1.14; p = .349, η2 = .039) (see Figure 1b). No group
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difference in overall pain intensity ratings was observed (F(1,62) = 3.36, p = .072, η2 = .051).
Finally, no effect of the covariate clinical pain was observed (F(8,496) = 2.32; p = .094, η2 =
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.036).
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Diagnostic Accuracy
Table 2 displays sensitivity and specificity values derived from the logistic regression
analysis performed to predict FM vs. RA group membership using each evoked pain measure.
Overall accuracy for group classification was considerably higher for SREP (Beta=-3.09,
S.E.=0.78, Wald=15.53, p<0.001) than for TSP (Beta=-0.95, S.E.=0.31, Wald=9.26, p=0.002).
To determine whether SREP sensitization accounted for significant variance explained beyond
that accounted for by TSP, a sequential logistic regression was conducted, entering TSP in the
first step, and adding SREP sensitization in the second step. SREP accounted for significant
additional variance in group discrimination ability relative to that accounted for by TSP alone
(Beta = -2.98, S.E.=0.81, Wald=13.47, p<0.001).
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Both individual SREP and TSP models resulted in significantly higher group discrimination
accuracy than pain threshold (Beta=0.31, S.E.=0.16, Wald=3.71, p=0.054) or tolerance
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(Beta=0.10, S.E.=0.11, Wald=0.78, p=0.377). To facilitate the comparison of between-group
overlap between dynamic evoked pain measures, a set of box and whisker plots for TSP and
SREP were generated (Figure 2). A lower overlap in distributions was observed for SREP
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sensitization than TSP. All FM patients, except one, had greater SREP sensitization values than
the mean of SREP in the RA group, and all RA patients had a SREP sensitization value lower
than the mean of FM group. Eight FM patients (22.9%) had lower TSP values than the mean of
TSP in the RA group, with five RA patients (16.67%) displaying a greater TSP value than the
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mean of the FM group.

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Test-Retest Reliability
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Table 3 shows intraclass correlation coefficients (ICCs) for repeated measures over
sessions and the associated 95% CIs in the FM and RA groups. According to ICC interpretation
guidelines (42), test-retest reliability in FM was moderate for TSP (0.74), good for SREP
sensitization (0.80), and excellent for pain threshold (0.95) and pain tolerance (0.90). Test-retest
reliability in the RA group was poor for TSP (0.49), moderate for SREP sensitization (0.68), and
good-excellent for pain threshold (0.89) and pain tolerance (0.87). Fisher´s Z statistic between
ICC coefficients for TSP and the static evoked pain measures (pain threshold and tolerance)
showed significant differences in both groups (all Z‟s > 2.17, all p’s< 0.05). Similarly, Fisher´s Z
statistic between ICC coefficients for SREP versus the static evoked pain measures were
significant in both groups for pain threshold (all Z‟s > 2.18, all p’s< 0.05), and marginally
significant in both groups for pain tolerance (all Z‟s > 1.49, all p’s< 0.07). However, the
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comparison between TSP and SREP ICC coefficients did not reach statistical significance in
either group (Z = 0.68, p = 0.49 for FM; Z = 1.08, p = 0.28 for RA).
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Associations between Evoked Pain Measures
In FM patients, pain threshold correlated positively with pain tolerance (r = .54 p = .001),
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but neither of these two static evoked pain indices were associated with TSP or SREP (all
r‟s<.25, all p’s > .150). TSP correlated positively with SREP sensitization in the FM group (r =
.47 p = .005). In RA patients, pain threshold also correlated positively with pain tolerance (r =
.60 p < .001), but neither of these measures were associated with TSP or SREP (all rs<.16, all p’s
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> .389). TSP was not significantly correlated with SREP sensitization in the RA group (r = .22, p
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= .255).
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DISCUSSION
A clear sensitization response to the SREP protocol was observed in FM patients, but was
absent in RA patients. This result corroborated our previous SREP study, in which a pattern of
increased subjective pain ratings was observed in FM patients, whereas no increase was observed
in healthy participants (31). Analogously, the increase in TSP was significantly greater in FM
than RA patients. Unlike the SREP protocol, in which no pain sensitization was observed in RA
patients, TSP was observed both in FM and RA, which is congruent with previous studies
showing the TSP phenomenon (although with different degrees of intensity) in patients with
other pain conditions (27-28). While speculative, the current findings suggest the possibility that
SREP sensitization might constitute a useful marker for the differentiation between central and
peripheral pain conditions. Future studies including other chronic pain conditions known to be
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characterized by altered central pain processes (e.g., temporomandibular disorder) could help
confirm the specificity of SREP as a marker of central sensitization.
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The overall mean subjective perceived pain intensity across trials was significantly
greater in FM than RA for TSP, but this difference only was marginally significant (r = .072) for
SREP sensitization. This can be explained by the use of stimulus pressures adapted to
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individual´s pain sensitivity to generate SREP sensitization. However, both indices were greater
in FM than RA patients. To the extent that TSP and possibly SREP reflect central sensitization,
these findings support a key role of central sensitization in FM pain, whereas peripheral pain
inputs may contribute to a relatively greater extent in RA pain (1).

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Pain threshold and tolerance were significantly associated with each other. Nevertheless,
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no relation was found between these static evoked pain measures and SREP or TSP. This lack of
relation between static and dynamic indices such as TSP (12,43) and SREP sensitization (31) has
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been previously observed. SREP and TSP were moderately associated in FM, but not in RA,
which might also support potentially different mechanisms contributing to the two dynamic
indices. In addition, it should be noted that these dynamic indices displayed a high level of
unique variance (78%). The high level of independence between static and dynamic pain indices
might also reflect their different underlying mechanisms. Static pain measures, as indices of
overall evoked pain sensitivity, reflect the combined effects of descending pain inhibition and
ascending pain facilitation processes, whereas the dynamic pain measures likely reflect primarily
the latter process (sensitization).
Higher levels of catastrophizing, anxiety and depression, and greater regular use of
antidepressant/anxiolytic medication were observed in FM compared to RA patients. This is
consistent with the frequent reporting of adverse experiences and co-morbid symptoms in
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centralized pain conditions such as FM (44) relative to RA patients or healthy individuals (45-
46). However, none of these potential confounds factors influenced the group differences in TSP
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or SREP responses.
The physiological mechanisms underlying TSP have been widely studied. The increase in
perceived pain intensity with rapidly repeated stimuli had been attributed to wind-up processes
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associated with increased activity of dorsal horn neurons to repeated quickly stimulation (19-21).
TSP mainly reflects central sensitization involving unmylienated C fibers (47). However, TSP
can be evoked at frequencies lower than 0.33 Hz, with some reports obtaining windup effects at
frequencies as low as 0.08 Hz (32). The SREP protocol, in contrast, applies repeated stimuli at a
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rate lower than any existing TSP protocol (0.03 Hz). While SREP might reflect some of the
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same mechanisms involved in TSP, findings regarding the lower stimulus frequency required to
elicit SREP sensitization, the different group associations between SREP and TSP, or the high
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level of non-shared variance between them suggest the possibility that mechanisms underlying
these two dynamic pain indices may differ. We hypothesize that mechanisms underlying SREP
might be related to those underlying aftersensation phenomena. In the context of TSP
procedures, aftersensations are defined as sensations that persist beyond the last stimulus of the
TSP series (23). These aftersensations have in common with SREP sensitization that: (1) pain is
reported approximately 30 seconds after the pain stimulus, and (2) they are more closely
associated with clinical pain levels than TSP itself (23, 31). It has been suggested that
aftersensations mainly depend on after-discharges of dorsal horn neurons following repetitive C-
fiber activation (23). The similarity of SREP sensitization and aftersensations further suggest that
SREP may be dependent on central rather than peripheral factors. As such, SREP sensitization
may be used as a protocol complementary to other pain sensitization measures such as TSP in the
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assessment of FM.
There have been numerous attempts to identify valid markers of central sensitization to
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facilitate the diagnosis of FM and better understand its‟ mechanisms. TSP has been
conceptualized as a central sensitization index of potential utility in understanding and
diagnosing FM (23). In our previous work, the SREP protocol showed a high diagnostic
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accuracy (85.4%) in differentiating between FM patients and healthy individuals, an accuracy
that was considerably lower for standard pain threshold and tolerance measures (70.8% and
68.8% respectively) (31). In the current study, SREP sensitization allowed for a substantially
larger percentage of correct classifications of FM versus RA status (87.7%) relative to TSP

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(64.6%), pain threshold (64.6%) or pain tolerance (52.3%). This high level of discrimination
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using SREP was observed both for sensitivity (0.89) and specificity (0.87). SREP was associated
with lower rates of false positives in discriminating FM versus RA compared to pain threshold or
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pain tolerance. Similarly, SREP produced considerably lower rates of false negatives compared
to TSP. Finally, the SREP sensitization measure exhibited less between-group overlap in its
distribution compared with TSP. Taken together, the current findings suggest that SREP may
serve as an index of pain sensitization characterizing FM, allowing for a high level of diagnostic
discrimination. Despite the good diagnostic accuracy of Quantitative Sensory Testing (QST)
protocols (including TSP and pain threshold/tolerance) in detecting FM (48), the apparently
better accuracy of SREP sensitization suggests that its inclusion in diagnostic protocols could
complement currently used measures and enhance diagnostic accuracy.
With respect to reliability in the FM group, the ICC for TSP approached a good level of
reliability (0.74). This value is similar or slightly lower than the degree of test-retest reliability
found in other studies (24-25,49). However, to the best of our knowledge, no study has evaluated
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reliability of TSP in patients with chronic pain. The use of chronic pain patients in our study,
instead of healthy participants, might explain some slight variation in reliability values of TSP in
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our study in comparison with previous ones. It may also relate to the use of mechanical stimuli
in the current study versus thermal stimuli in TSP protocols in prior reliability studies. Reliability
of mechanical TSP in this study might have been increased by conducting multiple TSP series
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(23). In comparison, SREP sensitization showed directionally greater test-retest reliability than
TSP, achieving a good reliability (0.80), although the difference in reliability coefficients did not
reach significance. As for TSP, reliability of the SREP index may be improved by employing
more than a single SREP series. Moreover, test-retest reliability for SREP sensitization in RA
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group was also greater (0.68) than for TSP (0.49). Excellent test-retest reliability was found for
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pain threshold and tolerance, as has been reported previously in several studies with healthy
individuals and patients with different pain conditions (25,49-50). The overall pattern of test-
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retest reliability findings is consistent with previous results (12), which also reported greater
long-term reliability for static pain measures than for dynamic measures like TSP or conditioned
pain modulation. However, it is important to note that despite higher test-retest reliability for
these static pain measures, diagnostic accuracy for them was clearly lower than for either
dynamic measure tested. The SREP protocol exhibited by far the highest overall accuracy,
sensitivity, and specificity of all measures obtained, including TSP. Based on the observed
pattern of findings, static pain measures might appear to be most useful to examine changes in
pain processing when high reliability is paramount (e.g., before and after an intervention), while
dynamic pain indices might prove especially useful for classifying chronic pain conditions and
detecting potentially contributory mechanisms.
The etiology of RA is mainly related to peripheral factors, rather than central
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sensitization, as is likely the dominant factor in FM (1). However, persistent inflammation and
mechanical damage in affected tissues of RA patients might be expected in some cases to drive
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alterations in central pain processing relative to individuals not experiencing chronic pain.
Absence of a non-pain control group in the current study makes it impossible to determine
whether the RA group displayed elevated TS relative to controls, which would indicate some
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degree of central sensitization (although less than in FM) even in this group. If this were the
case, the total absence in RA patients of the SREP sensitization that was observed in the FM
group might suggest that the SREP protocol does not tap into the same aspects of central
sensitization that are assessed by traditional TSP protocols. Moreover, the greater accuracy of
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SREP sensitization, in comparison with TSP, in discriminating between FM and RA patients

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might suggest a stronger relation between enhanced central sensitivity and SREP than is
observed for TSP, whose relationship with C-fiber mediated central sensitization has been
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previously demonstrated (47). Whether elevated SREP sensitization is a hallmark specifically of
FM, or rather, is characteristic of centralized chronic pain conditions more generally, remains to
be determined in future studies. For example, it would be useful to compare degree of SREP
sensitization in FM patients to that observed in patients experiencing temporomandibular
disorder or chronic nonspecific low back pain.
This study had several limitations. First, our results are limited only to women, without
being generalizable to men. The fact that all participants were women may have produced
greater variability in pain sensitivity between sessions which in turn could potentially reduce
reliability, since it is well know that the menstrual cycle influences pain perception (51).
Although hormonal disorders were an exclusionary criterion, menstrual cycle was not controlled
and some participants were premenopausal whereas others were postmenopausal. Given that
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information on hormonal medication use was not obtained, this is another factor that could
potentially increase variability in outcomes across sessions and reduce reliability. Second, a
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slightly larger sample size would have been optimal to reduce the probability of type I and II
errors. Another relevant methodological difference between the two protocols is the use of
different forms of pressure stimulation: blunt pressure for SREP and punctate pressure for TSP.
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Blunt pressure is more similar than punctate pressure to the typical manual palpation used in
traditional FM diagnosis. Finally, our study did not examine directly the physiological
mechanisms underlying SREP. Therefore, despite the SREP protocol being compared directly in
the current work to a well-known dynamic evoked pain index of central sensitization (TSP), the
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specific underlying mechanisms of SREP sensitization need further investigation. Inclusion of a

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healthy non-pain control group in future studies would aid in interpretation of comparative
results across chronic pain conditions with different hypothesized mechanisms.

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In conclusion, SREP sensitization constitutes a novel dynamic evoked pain index that
seems to reflect pain sensitization processes and that allows for a high level of diagnostic
accuracy for identifying central pain conditions like FM with a good reliability. Future research
is needed to study the utility of adding SREP to standard pain evaluation protocols. Current
findings indicate that further investigation of the SREP protocol appears warranted.
Acknowledgements: This research would not have been possible without the collaboration of
the Fibromyalgia (AFIXA) and Rheumatoid Arthritis (AJEAR) associations of Jaén.
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FIGURE LEGENDS
Figure 1a. Mean (+SE) evoked pain ratings (0-10 scores) over repeated stimuli as a function of
group across the 10 TSP trials (mean of two repetitions).
Figure 1b. Mean (+SE) evoked pain ratings (0-10 scores) over repeated stimuli as a function of
group across the 9 SREP trials.
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Figure 2. Between-groups overlap for TSP (left) and Slowly Repeated Evoked Pain (SREP)
sensitization (right).
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Figure 1
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Figure 2
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Table 1. Demographic, psychological and evoked pain measures in Fibromyalgia and
Rheumatoid Arthritis patients.
Variables Fibromyalgia (n=35) Arthritis (n=30) t or χ² p η2
Age, years 53.11±8,28 53.07±10.55 .020 .984 <.001

BMI, kg/m2 27.28±4.41 26.59±5.41 .016 .987 <.001
Between-session interval (days) 5.57±1.12 5.90±1.09 2.487 .478 .196
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Catastrophizing (CSQ) 19.20±12.63 10.27±11.46 2.965 .004 .122
Anxiety (HADS) 17.65±4.36 11.60±7.17 4.182 <.001 .217
Depression (HADS) 14.23±5.90 8.20±5.91 4.101 <.001 .211
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Clinical Pain (total MPQ) 74.77±42.06 46.73±37.27 2.823 .006 112
Antidepressant use (%) 28 (45.83) 7 (23.33) 20.872 <.001 .567
Anxiolytic use (%) 28 (58.33) 9 (30.00) 16.470 <.001 .503
Analgesic (%) 27 (77.14) 26 (86.67) 0.973 .359 .122
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Opiate use (%) 15 (42.86) 8 (26.67) 1.212 .202 .169
Threshold [A] 2.26±1.91 3.17±1.58 - 2.074 .042 .064
Threshold [B] 2.32±1.17 3.19±1.46 - 2.154 .035 .069
Tolerance [A] 7.02±2.74 7.54±1.86 - .905 .382 .012
Tolerance [B] 6.65±2.51 7.33±1.80 - 1.248 .217 .024
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TSP [A] 1.67 ±1.17 0.84±0.80 3.706 .001 .170

TSP [B] 1.79±1.47 0.53±0.74 4.433 <.001 .221
SREP sensitization [A] 1.59±1.11 -0.11±0.70 7.252 <.001 .455
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SREP sensitization [B] 1.52±1.08 0.00±0.50 7.414 <.001 .441

SREP Stimulus pressure [A] * 3.75±1.91 4.53±1.51 - 1.822 .073 .050
SREP
(C) (C)Stimulus pressure [B] * 3.67±1.88 4.48±1.45 - 1.928 .058 .056
A
Note. Means±SD and results of the group comparison (t or χ², p, and η2). BMI= Body Mass
For medication use, it is indicated the number of participants and percentage in brackets.
Index, TSP = Temporal Summation of Pain, SREP = Increase in pain ratings generated by
Slowly Repeated Evoked Pain protocol. [A] Test Session. [B] Retest Session.
* Individually calibrated stimulus pressure for the SREP procedure in Kg/cm2.
Table 2. Sensitivity and specificity values and overall accuracy for the discrimination between
FM and RA patients for Slowly Repeated Evoked Pain (SREP) sensitization, Temporal
Summation of Pain (TSP), and Pain Threshold and Tolerance.
TSP SREP sensitization Threshold Tolerance
Sensitivity 0.57 0.89 0.74 0.77
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Specificity 0.73 0.87 0.53 0.22
Overall
64.6% 87.7% 64.6% 52.3%
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Accuracy EP
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Table 3. ICC coefficients across sessions to evaluate test-retest reliability of Temporal
Summation of Pain (TSP), Slowly Repeated Evoked Pain (SREP) sensitization, Pain Threshold
and Tolerance.
Fibromyalgia Rheumatoid Arthritis
ICC coefficient 95% CI ICC coefficient 95% CI
TSP 0.73 0.46 – 0.86 0.49 0.07 – 0.76
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SREP 0.80 0.61 – 0.90 0.68 0.32 – 0.85
0.91 – 0.98 0.77 – 0.95
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Threshold 0.95 0.89
Tolerance 0.90 0.81 – 0.95 0.87 0.73 – 0.94
Note. All ps <.001. ICC = Intraclass correlation.

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Psychosomatic Medicine

Author’s Accepted Manuscript

Article Title: Slowly Repeated Evoked Pain (SREP) as a

Authors: Pablo de la Coba, Stephen Bruehl, Carmen M.

Received Date: Nov. 7, 2017

SLOWLY REPEATED EVOKED PAIN (SREP) AS A MARKER OF

CENTRAL SENSITIZATION IN FIBROMYALGIA: DIAGNOSTIC

ACCURACY AND RELIABILITY IN COMPARISON WITH TEMPORAL

Gustavo A. Reyes del Paso1

Address of the corresponding author: Pablo de la Coba. Departamento de Psicología.

Universidad de Jaén. 23071 Jaén, Spain. E-mail: pcoba@ujaen.es Fax: +34953211881.

Economy and Competitiveness, co-financed by FEDER funds (Project PSI2015-69235-P), and

Ministry of Education, Culture and Sport.

Conflict of interest statement

Abbreviated running head: SREP as a marker of central sensitization

summation of pain (TSP), a standard index of central sensitization. Methods: Thirty-five

fibromyalgia (FM) and 30 rheumatoid arthritis (RA) patients completed, in pseudorandomized

between FM and RA patients. Test-retest reliability of SREP sensitization was good in FM

identifying FM patients compared to a standard TSP protocol. Further research is needed to

KEYWORDS: Fibromyalgia, Central Sensitization, Temporal Summation of Pain, Pain

Threshold, Diagnostic Accuracy, Test-Retest Reliability.

ACR = American College of Rheumatology

ARA = American Rheumatology Association

CSQ = Coping Strategies Questionnaire

HADS = Hospital Anxiety and Depression Scale

MPQ = McGill Pain Questionnaire

QST = Quantitative Sensory Testing

SREP = Slowly Repeated Evoked Pain

TSP = Temporal Summation of Pain

VAS = Visual Analogue Scale

response to pain-related upregulation of ascending facilitation pathways (2-4), and deficits in

descending spinal inhibitory influences have been found in FM (5-7).

responsiveness during repetitive stimulus conditions designed specifically to assess ascending

in FM (22-23). However, although reliability of TSP seems to be acceptable (24-25), its

diagnostic accuracy in FM may not be optimal, since a significant proportion of FM patients do

additional research to characterize the SREP protocol appears justified.

SREP sensitization in healthy individuals in our prior work (31).

hypothesized that if SREP sensitization were mediated by central mechanisms, significantly

different pain mechanisms across the two conditions.

TSP protocols in FM patients.

stimuli 5 seconds in duration with an inter-stimulus interval of 30 seconds. To assess subjective

with the anchors being “No Pain” and “Extremely Painful.”

Assessment of clinical and psychological factors

possible confounding influences of these clinical-psychological factors. Clinical pain was

Anxiety and Depression subscales) (38).

(including regular medication use), and administered the clinical-psychological measures.

within-participants and between sessions).

Intensity = Threshold + 1.25*(DF/4); where DF = Tolerance–Threshold (39). Ten minutes after

Derivation of SREP & TSP indices

greater pain sensitization.

covariate in primary analyses. To address the possible impact of individual differences in

first subjective pain rating of each TSP series as a covariate.

The Greenhouse-Geisser correction was used for possible violations of sphericity

coefficients were tested for significance through Fisher´s Z statistic.

antidepressants, anxiolytics, analgesic/opiate drugs) included as covariates. These analyses failed

0.18, p = 0.86 for FM; t = -0.42, p = 0.68 for RA).

in demographics or analgesic/opiate use. However, levels of clinical pain, catastrophizing,

anxiety, depression, and antidepressant/anxiolytic use were higher in FM than RA patients.

(TSP and SREP) were greater in FM than in RA patients.

Pain Ratings during TSP versus SREP

(Beta = -2.98, S.E.=0.81, Wald=13.47, p<0.001).

accuracy than pain threshold (Beta=0.31, S.E.=0.16, Wald=3.71, p=0.054) or tolerance

mean of the FM group.