Research Paper

Deficient conditioned pain modulation after spinal cord injury correlates with clinical spontaneous pain measures a,b Sergiu Albua, Julio Gomez-Soriano ´ , Gerardo Avila-Martina, Julian Taylora,*

Abstract The contribution of endogenous pain modulation dysfunction to clinical and sensory measures of neuropathic pain (NP) has not been fully explored. Habituation, temporal summation, and heterotopic noxious conditioning stimulus–induced modulation of tonic heat pain intensity were examined in healthy noninjured subjects (n 5 10), and above the level of spinal cord injury (SCI) in individuals without (SCI-noNP, n 5 10) and with NP (SCI-NP, n 5 10). Thermoalgesic thresholds, Cz/AFz contact heat evoked potentials (CHEPs), and phasic or tonic (30 seconds) heat pain intensity were assessed within the C6 dermatome. Although habituation to tonic heat pain intensity (0-10) was reported by the noninjured (10 s: 3.5 6 0.3 vs 30 s: 2.2 6 0.5 numerical rating scale; P 5 0.003), loss of habituation was identified in both the SCI-noNP (3.8 6 0.3 vs 3.6 6 0.5) and SCI-NP group (4.2 6 0.4 vs 4.9 6 0.8). Significant temporal summation of tonic heat pain intensity was not observed in the 3 groups. Inhibition of tonic heat pain intensity induced by heterotopic noxious conditioning stimulus was identified in the noninjured (229.7% 6 9.7%) and SCI-noNP groups (219.6% 6 7.0%), but not in subjects with SCI-NP (11.1% 6 8.0%; P , 0.05). Additionally, the mean conditioned pain modulation response correlated positively with Cz/AFz CHEP amplitude (r 5 0.8; P 5 0.015) and evoked heat pain intensity (r 5 0.8; P 5 0.007) in the SCI-NP group. Stepwise regression analysis revealed that the mean conditioned pain modulation (R2 5 0.72) correlated with pain severity and pressing spontaneous pain in the SCI-NP group. Comprehensive assessment of sensory dysfunction above the level of injury with tonic thermal test and conditioning stimuli revealed less-efficient endogenous pain modulation in subjects with SCI-NP. Keywords: Tonic thermal test stimuli, Pain habituation, Temporal summation, Conditioned pain modulation, Endogenous pain

modulation, Cz/AFz noxious evoked potentials, Contact heat evoked potentials, Quantitative thermal sensory testing, Pain severity, Pain interference, Neuropathic pain symptoms

1. Introduction Neuropathic pain (NP) is a common complication of spinal cord injury (SCI), which includes an important psychosocial component.71,82 Quantitative sensory testing (QST) in subjects with spinal cord injury with neuropathic pain (SCI-NP) has revealed change in nociception at,11,21,23,24 below,11,24,30,76,87 and above the SCI level,20,23,40 reflecting several pathophysiological mechanisms.22,33,63 However, increased pain intensity to noxious stimuli in subjects with SCI-NP 21,23,24 may also reflect change in the endogenous pain modulation (EPM) system related to cognitive function.67 Pathophysiological mechanisms of EPM dysfunction, defined in this study as enhanced temporal summation, reduced habituation and deficient conditioned pain modulation (CPM), Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a

Sensorimotor Function Group, Hospital Nacional de Paraplejicos ´ SESCAM, Finca “la Peraleda,” Toledo, Spain, b Escuela de Enfermerı´a y Fisioterapia de Toledo, Universidad de Castilla La Mancha, Toledo, Spain. S. Albu is now with the Department of Psychology, Texas A&M University, TX, USA *Corresponding author. Address: Sensorimotor Function Group, Hospital Nacional de Paraplejicos, Finca “La Peraleda” s/n, 45072 Toledo, Spain. Tel.: (34) 925 247700 Ext 109; fax: (34) 925 247745. E-mail address: [email protected] (J. Taylor). PAIN 156 (2015) 260–272 © 2015 International Association for the Study of Pain http://dx.doi.org/10.1097/01.j.pain.0000460306.48701.f9

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have all been identified during NP.67 Enhanced temporal summation in response to repeated noxious stimuli has been shown at, below,17,18,21,87 and above the level of SCI.23 Furthermore, application of tonic test heat stimuli has revealed widespread central sensitization at and below the level of a spinal cord cavernous hemangioma.24 Regarding habituation, repeated application of contact heat stimuli measured as evoked potential amplitude suggests loss of efficient EPM in subjects with SCI-NP,40 which is often replaced with facilitatory pain modulation, as observed in several NP pathologies.67 Originally noxious reflex studies were used to support dysfunction of the EPM system after spinal injury,6,57 but loss of efficient CPM in subjects with SCI-NP in response to the application of heterotopic conditioning stimuli has not been demonstrated. Psychophysical studies have contributed to our understanding that several different NP pathologies are characterized by central sensitization to noxious stimuli,84 which can be measured as enhanced temporal summation54 and loss of habituation12 to test stimuli, and less-efficient CPM mediated by conditioning stimuli.85 Neurophysiological studies that have measured noxious evoked potentials have also been performed to identify mechanisms of habituation,12,27,40,53 temporal summation,68 and CPM.35,78 Neuroimaging techniques have also implicated several cortical and subcortical structures that may mediate EPM, including the primary and secondary somatosensory area, PAIN®

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anterior cingulate, orbitofrontal cortex, amygdala, and mesencephalic pontine reticular formation.13,42,49 The aim of this study was to characterize the specific role of loss of habituation, increased temporal summation, and deficient CPM in mediating SCI-NP using tonic heat test stimuli,24 and to establish their relationship with basal thermoalgesic QST, Cz evoked potentials, clinical pain measures and symptoms.2 Improved psychophysical and neurophysiological characterization of EPM dysfunction and the role of each process in subjects with SCI-NP would support the hypothesis that change in the central processing of tonic noxious stimuli is a key pathophysiological mechanism in subjects with central NP.

2. Materials and methods This study protocol was approved by the local Clinical Research Ethics Committee (Approval number 34; 2006) and was performed according to the most recent Helsinki Declaration guidelines. Written informed consent was obtained from all recruited subjects after careful explanation of the experimental procedures. The 3 experimental groups included subjects without SCI (noninjured group) and individuals with SCI, either without neuropathic pain (SCI-noNP) or with NP (SCI-NP), according to the inclusion criteria described below. The inclusion criteria for the noninjured group (n 5 10) were defined: as absence of previous or actual symptoms or signs of neurological disease or chronic pain. The exclusion criteria for the noninjured group included: absence of trauma to the central or peripheral nervous system, or pain present during movement, inflammation, or local tissue damage. 2.1 Subjects with SCP The SCI grade and its neurological level were assessed according to the American Spinal Cord Injury Association Impairment Scale (AIS)46 and the International Standards for Neurological Classification of SCP.37 An experienced neurologist (S.A.) recruited subjects aged between 18 and 70 years with SCI. The inclusion criteria for subjects with SCI required an AIS A-D grade, traumatic or nontraumatic etiology, and a neurological level of lesion located between Th2-L1. The inclusion criteria for NP included the presence of daily nonevoked and/or evoked pain during the previous 8 weeks. Specifically, central NP was diagnosed based on the 7-day pain intensity measured on the 0 to 10 numerical rating scale (NRS, see below) in addition to classification of the NP subtype either as at-level or below-level according to the International Spinal Cord Injury Pain criteria. 8 The grading system for definite NP was applied.22,73 Subjects were recruited into the study if untreated or were following a constant 2- to 4-week medication for their pain with antiepileptics (gabapentin or pregabalin), antidepressants (amitriptyline), anxiolytics (lorazepam), or opioids (tramadol). The exclusion criteria for subjects with SCI included were: cauda equina injury (neurological level at or below L2) or brain injury. Subjects with pain related to peripheral nervous system injury or evoked during movement, inflammation, or local tissue damage were also excluded from the study.22 Subjects with a mild pain intensity score of less than 2 rated on the NRS (see below) with only 1 NP symptom identified with the Neuropathic Pain Symptom Inventory (NPSI, see below) were not recruited. Accordingly, individuals were finally recruited and assigned to the SCI-noNP group (n 5 10, Table 1) and the SCI-NP group (n 5 10, Table 2).

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2.2. Experimental sessions All subjects participated in three 45-minute sessions performed on different days during the same week. During the first session, subjects completed several health-related questionnaires. This step was followed by complete QST of thermal thresholds evoked from the dominant forearm volar area that corresponded to the C6 dermatome. During the second session, the heat temperature at which a pain rating of 3/10 (pain-3) was identified for each individual tested over the thenar eminence (C6) of the dominant hand. The subject was asked to rate the tonic heat pain intensity during the 30-second pain-3 test stimulus to identify temporal summation or habituation. Conditioning paradigms were then applied to the contralateral hand, and the subject was asked to rate the tonic heat pain intensity after the heterotopic stimuli. The conditioning paradigms included a 33˚C conditioning stimulus (CS) followed by a 12˚C CS. On the last session, Cz/AFz contact heat evoked potentials (CHEPs) were evoked from the C6 dermatome with a computer-controlled thermofoil heating device and the associated evoked heat pain (EvHP) intensity was also evaluated.

2.3. Hospital Anxiety and Depression Scale, and pain questionnaires The Hospital Anxiety and Depression Scale (HADS) questionnaire was applied to all the experimental groups to identify the grade of anxiety disorder (7 items) and depression (7 items) measured using a self-report 4-point NRS (range, 0-3). The total score for each domain was calculated as the sum of the respective 7 items (ranging from 0-21), with the cutoff scores considered as 8 to 10 for doubtful cases and a score of 11 or higher for valid cases of anxiety or depression.32,64 The Brief Pain Inventory (BPI) was used to evaluate the subject’s perception of NP severity and its interference with several dimensions of daily life (physical activity, work, mood, ability to walk, sleep, and their relationship with other people) during the previous week.4 The scores were rated with a 0 to 10 NRS (pain severity was rated from “0” for “no pain” to “10” as “worst pain imaginable,” whereas pain interference was rated from “0” for “not affected me” to 10 defined as “affected me completely”). Neuropathic pain symptoms were assessed with the NPSI to detect paraesthesia/dysaesthesia, evoked pain, nonevoked ongoing pain, and paroxysmal pain in the SCI-noNP and SCINP groups, using a validated questionnaire (provided by Dr Javier Rejas, Pfizer Spain). These symptoms were rated with the 0 to 10 NRS, where 0 was defined as “no symptom” and “10” as the “worst symptom imaginable,” where “symptom” was replaced with more specific nouns. The 6-item subdivision of the validated Spanish version of the Coping Strategies Questionnaire was used to assess adoption of pain catastrophizing as a coping strategy in the experimental groups.58 The catastrophizing score was measured with the Pain Catastrophizing Helplessness Subscale, as used previously by the research group to assess coping strategy adoption during the first year in subjects with SCI-NP.71 This information was evaluated by asking participants to recall their past painful experiences and to indicate the degree to which they experienced the 6 thoughts or feelings when perceiving pain, measured on a 6-point Likert scale, where 0 represented “not at all” and “6” represented “all the time.” The Pain Catastrophizing Helplessness subscore was calculated as the total sum of 6 item responses.

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Table 1

Demographic and clinical characteristics of pain-free subjects with SCI. Subject number

Age, yr

1 2 3 4 5 6 7 8 9 10

44 41 39 47 50 48 39 42 26 52

Gender

AIS (A-D)

SCI Neur. level

Etiology (T/NT)

F M M M M F M F M F

D A A A A A A A C C

Th 6 Th 4 Th 10 Th 12 Th 3 Th 12 L1 Th 5 Th 2 Th 12

NT T NT T T T T NT T T

Time since SCI, mo 2 13 5 5 11 6 1 2 9 5

Medication – – – – – – – – – TC

AIS, American Spinal Cord Injury Association Impairment Scale; F, female; L, lumbar; M, male; Neur. level, neurological level of injury; NT, Nontraumatic; SCI, spinal cord injury; T, traumatic; TC, tricyclic antidepressant (amitriptyline); Th, thoracic.

3. Thermal QST Methodological details for thermal QST have been described previously.2 Subjects were seated comfortably in a quiet room at a stable ambient temperature of 22 to 23˚C so that thermal perception and pain thresholds could be assessed using a computer-controlled thermofoil heating system (Pain and Sensory Evaluation system, Pathway System, Serial Number: 23, Software version: 3.5, Firmware version: 2.4.3; Medoc Ltd, Ramat Yishai, Israel). Warm and cold detection thresholds (WDT and CDT, respectively) and heat and cold pain thresholds (HPT and CPT, respectively) were assessed using the method of limits59 from the nonglabrous surface of the dominant forearm, which corresponded to the C6 dermatome. All thresholds were assessed by delivering thermal stimuli from a 32˚C baseline, at a 1˚C/s heating or cooling rate, applied at a minimum interstimulus interval of 4 to 6 seconds over the explored dermatome. The temperature safety limits were set at 50.5 and 0.0˚C for heat and cold stimuli, respectively. Threshold values were recorded when the subject pressed the control button as they perceived a change in temperature (warm and cold detection thresholds) or at the beginning of pain sensation (HPT and CPT). During the QST, the subjects were blinded from the operator screen. Average thermal detection and pain thresholds were calculated after presentation of 4 individual stimuli.

3.1. Determination of the temperature for individual “pain-3” tonic heat pain intensity The subject was asked to perform a short training session with three 7-second contact heat stimuli ranging from 39 to 49˚C and applied to the dominant thenar eminence corresponding to the C6 dermatome, so that they familiarized themselves not only with the testing procedure but also the range of perceived sensation (Fig. 1). This training included understanding how to rate pain intensity with the 0 to 10 NRS, where 0 represented “no pain” and “10” the “worst pain imaginable,” as had been explained with previous instructions.60 Initially, the individual temperature at which the heat stimulus induced a score of 6/10 on the 0 to 10 NRS, “pain-6,” was identified in the noninjured group and in subjects with SCI according to the protocol developed by Granot et al.26 However, in 2 of 3 subjects with SCI-NP (11 and 13 in Table 2), the 60second heat pain stimulus was not tolerated and was associated with a heat pain intensity of 9/10 (NRS) rated at 7 seconds, and were therefore unable to complete the “pain-6” stimulus. Therefore, a 7-second heat pain stimulus was then applied to evoke a “pain-3” intensity, which could be tolerated for at least 30 seconds by both the noninjured and SCI subjects (Fig. 1). This was achieved by increasing the temperature from the 42˚C baseline in 1 degree steps with a 1-minute interstimulus interval. Identification of the specific temperature for pain-3 intensity was

Table 2

Demographic and clinical characteristics of subjects with SCI and NP. Subject Age, number yr

Gender AIS SCI (A-D) Neur. level

Etiology (T/NT)

Time since SCI, mo

Time since Actual at/below- 7-d At/belowSCI pain, level NP intensity level NP mo (NRS) intensity (NRS)

BPI score SEV/INT (0-40/0-80)

11 12 13

40 41 60

M M F

D B B

Th 10 Th 4 Th 6

T T NT

5 42 7

4 38 5

7/0 5/5 9/0

7/0 5/7 7/0

28/50 27/60 26/34

14 15

37 28

M M

A A

Th 12 Th 10

T T

36 6

35 6

0/5 6/7

0/6 6/6

27/53 22/46

16

52

M

B

Th 5

T

90

70

0/3

0/7

24/63

17 18 19 20

42 26 46 45

M M M F

C A B A

Th 9 Th 12 Th 8 Th 12

T T NT NT

14 4.5 2.5 5

10 2.5 2.5 2.5

0/0 0/5 5/0 0/8

0/5 0/5 6/0 0/7

12/6 20/40 22/50 30/28

NPSI score BSP/ Medication PSP/PP/EP/PD (0-10) 7.0/6.5/4.5/0/2.0 5.0/7.0/4.0/4.7/0 9.0/9.0/8.0/0/ 10.0 5.0/8.0/2.0/0/4.5 8.0/6.0/3.0/2.3/ 8.0 9.0/4.5/9.5/6.7/ 10.0 0/0/6.0/0/4.0 7.0/0/9.0/1.7/7.0 0/4.0/3.5/7.3/3.5 5.0/9.0/0/0/6.5

– AC/AX/OP AC/AX AC/TC/AX TC/AX AC AC – – –

AC, anticonvulsant (pregabalin); AIS, American Spinal Cord Injury Association Impairment Scale; AX, anxiolytic (lorazepam); BPI, brief pain inventory; BSP, burning (superficial) spontaneous pain; EP, evoked pain; F, female; INT, pain interference; M, male; Neur. level, neurological level of injury; NP, neuropathic pain; NRS, numerical rating scale; NPSI, Neuropathic Pain Symptom Inventory; NT, nontraumatic; OP, opioid (tramadol); PD, paresthesia/ dysesthesia; PSP, pressing (deep) spontaneous pain; PP, paroxysmal pain; SEV, pain severity; SCI, spinal cord injury; T, traumatic; TC, tricyclic antidepressant (amitriptyline); Th, thoracic.

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Figure 1. Schematic of the tonic heat test and the contralateral thermal conditioning stimuli application. The 30-second tonic heat test stimulus was applied to the thenar surface of the hand at a temperature previously rated as 3/10 (pain-3) at 7 seconds with the numerical rating scale. Conditioned pain modulation of the tonic heat pain intensity was evaluated after immersion of the contralateral hand in water at 33˚C and 12˚C for 30 seconds.

reconfirmed by applying a heat stimulus at 1˚C below and above the individually rated suprathreshold temperature. Finally, the complete 30 second tonic heat pain stimulus at pain-3 was applied from a 35˚C baseline temperature, with a 1.0˚C/s rising rate followed by a falling rate of 8.0˚C/s. The 30 second pain-3 tonic heat pain stimulus was tolerated by all experimental groups. 3.2 CPM of the tonic heat pain test stimulus Tonic heat pain stimulation applied at pain-3 intensity to the skin of the dominant thenar eminence was rated at 10, 20, and 30 seconds with the 0 to 10 NRS (Fig. 1). Mean pain unpleasantness was rated immediately after termination of the 30–second pain-3 tonic heat stimulus. This stimulation protocol was used to identify evidence for both habituation and temporal summation to noxious stimuli in all experimental groups. The effect of CPM can last up to 60 minutes after application of the CS,55 which prevents the use of a randomized design. Therefore, after a 15minute rest period, CPM was addressed first by assessing tonic heat pain intensity immediately after application of the heterotopic 33˚C CS and 15 minutes later after application of the 12˚C CS. Heterotopic 33˚C and 12˚C CS were applied with the aid of a 15-L water bath (30 3 25 3 25 cm), which enabled immersion of the nondominant hand during 30 seconds (Fig. 1). Temperature was controlled with continuous immersion of a thermometer into the bath during the experiment. Subjects were previously told that they could remove their hand from the water bath if an extremely painful sensation was produced. Psychophysical rating of pain intensity and unpleasantness in response to both the test and conditioning stimuli was achieved using previous instructions learned during the training session.60 During immersion of the contralateral hand into the water bath, subjects were asked to rate pain intensity of the CS at 10, 20, and 30 seconds in addition to a final evaluation of pain unpleasantness. Tonic heat pain intensity assessed after application of the heterotopic CS was achieved by instructing the subjects to pay close attention to the test stimulus and to rate the pain induced at 10, 20, and 30 seconds and the mean unpleasantness after application.

3.3. Cz/AFz CHEPs and pain intensity Assessment of Cz/AFz CHEP amplitude and associated EvHP intensity was performed with the subjects placed in a supine position as described previously.2 Contact heat evoked potentials were evoked with 10 consecutive 70˚C/s heat ramp applied to the dominant hand over the C6 dermatomal site, from an actively controlled baseline temperature of 39.0˚C39 up to a maximum temperature of 51.0˚C, with a minimum interstimuli interval of 20 seconds using a computer-controlled thermofoil heating system (Pathway System, Serial Number: 23 Software version: 3.5, Firmware version: 2.4.3; Medoc Ltd, Ramat Yishai, Israel). Contact heat evoked potentials were recorded with 12.0- 3 0.4-mm (27 gauge) stainless steel subdermal needle electrodes (CareFusion Germany, Ref: 019-409800). An electrode was inserted into the scalp at the Cz-recording site according to the standard 10- to 20electrode configuration,5 with the common reference electrode inserted at AFz,34 and the ground electrode attached to the right ear. The thermode was applied to the C6 dermatome of the dominant hand and manually held in position. Subjects were instructed to keep their eyes closed in a fixed neutral position for at least 2 seconds after perception of each stimulus to reduce contamination of the CHEPs signal with eye muscle blink activity.2 Contact heat evoked potential data were recorded using an amplifier (Dual Bio Amplifier, ADInstruments, Ref: ML135, Australia) with a 0.1- to 100.0-Hz bandpass and a gain that permitted signal analysis with a 50-mV/division scale and a 1000millisecond window. CHEP data acquisition was performed with an analog–digital data conversion device (PowerLab 16SP, Ref: SP1347, ADInstruments, Australia) with a signal-recording software (Scope Version 3.6.10, ADInstruments, Australia). Patient’s familiarization with the CHEP protocol and associated EvHP evaluation was achieved by using 2 contact heat stimuli delivered initially without registering the evoked potentials. Evoked heat pain intensity (EvHP) was rated by the subjects according to their subjective pain perception associated with each CHEP heat stimulus using the 0 to 10 NRS, where 0 represented “no pain at all,” and 10 the “worst pain imaginable.”

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3.4. Data analysis Both the magnitude and percentage rate of habituation to pain intensity were measured during the tonic heat stimulus applied at the pain-3 temperature, and were calculated by subtracting the individual pain intensity at 30 seconds from perceived pain intensity at 10 seconds. For CHEP analysis, both the N and P waves were detected visually before the final analysis to exclude contaminated CHEP signals. Contact heat evoked potential parameters included N-wave latency (milliseconds) and N2/P2 peak-to-peak amplitude (mV). The data were averaged after 10 contact heat stimuli, except in the case of the measurement of habituation where the first and last CHEP were analyzed alone. The CHEP and associated EvHP habituation rate were also calculated for each subject as the percentage of the N2/P2 amplitude evoked after the last stimulus with respect to the N2/ P2 amplitude recorded after the first stimulus. Higher percentage CHEP and EvHP habituation rate corresponded to low level of habituation. Finally, the mean CPM response of the pain-3 tonic heat stimulus rated at 10, 20, and 30 seconds was calculated by normalizing the change in pain intensity rated after the 12˚C CS compared with the response obtained after 33˚C CS. Therefore, negative mean CPM response values reflected efficient CPM, whereas positive values revealed facilitation of the tonic heat pain intensity.

3.5. Statistical analysis Statistical analysis was performed with 2 commercial software packages (SPSS, version 17.0, SPSS Inc, Chicago, IL, and SigmaStat for Windows, Version 11, Systat Software Inc, San Jose, CA). Parametric variables were presented as mean and standard error (mean 6 SE), whereas nonparametric data were presented as median with the 25th to 75th interquartile range. For intergroup comparison of normally distributed variables, a 1-way analysis of variance (ANOVA) was performed, followed by a post hoc Bonferroni test. The variables’ time after SCI, HADS-A, HADS-D, tonic test heat pain unpleasantness, and CS pain intensity failed the Kolmogorov–Smirnov normality test, and as such were analyzed using nonparametric tests (Mann–Whitney rank-sum test and Kruskal–Wallis on ranks). Nonparametric Spearman correlations were performed to examine the possible relationship between pain measures of habituation and 12˚C CS–induced CPM, including their association with the other clinical parameters such as pain intensity and unpleasantness, anxiety, and depression. In all cases, the minimum probability level was defined as 0.05. Statistical analysis of tonic heat pain intensity rated by the 3 experimental groups during either the test or conditioning stimuli were analyzed with a 2-way repeated-measures ANOVA with the factors “group” (levels: noninjured, SCI-noNP, and SCI-NP groups) and “time” (levels: 10, 20, and 30 seconds). In addition, within-group analysis of the effect of the heterotopic CS on the pain intensity rated during the pain-3 tonic heat test stimulus was analyzed for the factors “paradigm” (levels: no CS, 33˚C CS, and 12˚C CS) and “time” (levels: 10, 20, and 30 seconds). Between-group analysis of the differences of mean CPM response evoked by the 12˚C CS was analyzed for the factor “group” (levels: noninjured, SCI-noNP, and SCI-NP groups) and “time” (levels: 10, 20, and 30 seconds). The post hoc Bonferroni test was applied to reveal specific differences between groups. Multiple linear regression statistics for the tonic pain outcome measures, including habituation and CPM, were analyzed first by identifying the contribution of each independent variable, or

a subset thereof, to best predict the dependent variable (best subset regression), followed by a forward stepwise regression analysis to find the model with the most suitable independent variables of those identified previously (SigmaStat for Windows, Version 11, Systat Software Inc). All regression models were based on defining 1 subset of effect terms to adequately account for the responses. Next, the “best” model of all possible subsets of effect terms was chosen according to computed statistics that explained the greatest amount of variation of the responses and maximal information criterion (largest adjusted R2 and Mallows’ Cp). A P value ,0.05 was considered statistically significant.

4. Results 4.1. Demographic and clinical characteristics Demographic and clinical data of the subjects recruited with SCI are presented for both the no pain group (SCI-noNP, Tables 1 and 3) and NP group (SCI-NP, Tables 2 and 3). No significant difference was observed for the mean age of participants between the noninjured (38.5 6 2.3 years, n 5 10, 2 women), SCI-noNP (42.8 6 2.3 years, n 5 10, 4 women), and SCI-NP groups (41.7 6 3.2 years, n 5 10, 2 women; P 5 0.58, Table 3). Furthermore, no difference was identified for the time after SCI between the pain-free group (SCI-noNP: 5.0, 2.0-8.0 months) and NP group (SCI-NP: 6.5, 5.036.0 months, P 5 0.17; Mann–Whitney U test). Both SCI groups included subjects with incomplete and complete grades of injury and a neurological level ranging from Th2 to L1. In the SCI-NP group, nonevoked NP was identified at-level (n 5 3), below-level (n 5 5), and both at-level and below-level (n 5 2, Table 2). The median time after NP onset was 5.5 (3.0-28.0) months, whereas the mean intensity for both the 7-day nonevoked at-level and below-level NP was 6.3 6 0.3 and 5.3 6 0.8 NRS units (Table 2). The mean BPI severity and interference scores were 23.8/40.0 and 43.0/80.0, respectively, for the SCI-NP group (Table 2). Examination of the NP symptoms in the SCI-NP group with the NPSI questionnaire (Table 2) revealed the presence of Burning (Superficial) spontaneous pain (5.5/10); Pressing (Deep) spontaneous pain (5.4/10); Paroxysmal pain (5.0/10); Evoked pain (2.3/10); and Paresthesia/dysesthesia (5.6/10). Five subjects with evoked pain were detected with the NPSI; 2 with at-level and below-level cold allodynia and another 3 individuals with a combination of cold and mechanical allodynia at and below the level of SCI. The SCI-NP group were characterized with a significantly higher pain catastrophizing helplessness score when compared with the noninjured subjects (P 5 0.05; ANOVA, Table 3). No difference was observed between the experimental groups for either anxiety or depression scores measured with the HADS questionnaire. Thermoalgesic QST also revealed similar WDT and CDTs or HPTs and CPTs within the C6 dermatome between groups (Table 3), including the temperature for pain-3 intensity. Finally, no difference between the experimental groups was demonstrated for either N2/P2 CHEP amplitude or N/P wave latency. 4.2. Tonic test heat pain habituation and temporal summation Pain intensity rated during the 30-second tonic heat stimulus revealed significant differences between the noninjured and SCI groups (P 5 0.001; ANOVA) including time as a factor (P 5 0.002; ANOVA, Table 3 and Fig. 2A). Indeed, the mean 30-second tonic

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Table 3

Demographic characteristics of the noninjured, SCI-noNP and SCI-NP experimental groups indicating information related to mood, thermal quantitative sensory tests, Cz evoked potentials, and CPM of tonic test heat pain intensity. Category Demographic Mood

Thermal QST

Cz CHEPs

CPM

Subcategory Age, yr Sex (F/M) HADS-A (0-21) HADS-D (0-21) PC-hs (0-36) WT, ˚C HPT, ˚C CT, ˚C CPT, ˚C N2/P2 CHEP amplitude, mV N-wave latency, ms P wave latency, ms CHEP habituation rate, % EvHP intensity (0-10, NRS) EvHP habituation rate, % Pain-3, ˚C Mean pain-3 tonic test heat pain INT (0-10, NRS) Mean pain-3 tonic test heat pain unpleasantness (0-10, NRS) Maximum 33˚C CS INT (0-10, NRS) Maximum 12˚C CS INT (0-10, NRS) Maximum 12˚C CS unpleasantness (0-10, NRS) Mean 10-30 s CPM, %

SCI-NP group

P

38.5 6 2.3 2/8 5 (3-6) 0.5 (0-4) 4.8 6 0.6 34.1 6 0.1 44.2 6 0.7 30.4 6 0.2 13.2 6 2.9 26.9 6 3.4 309 6 9 397 6 10 78.2 6 5.2 3.7 6 0.6 68.5 6 8.1 42.0 6 0.6 2.8 6 0.4 2 (1-3)

42.8 6 2.3 4/6 2.5 (1-5) 3.5 (2-5) 8.0 6 2.4 34.7 6 0.4 44.4 6 0.9 30.2 6 0.2 12.3 6 2.5 26.2 6 2.3 336 6 13 411 6 15 75.0 6 6.3 3.7 6 0.6 57.4 6 9.6 42.4 6 0.3 3.7 6 0.4 3 (2-3)

41.7 6 3.2 2/8 7 (4-11) 5.5 (0-8) 13.4 6 2.3* 34.5 6 0.3 45.4 6 0.7 30.1 6 0.3 8.9 6 2.5 27.1 6 3.2 349 6 13 425 6 16 74.7 6 3.8 3.6 6 0.6 71.6 6 9.6 42.7 6 0.7 4.6 6 0.6* 4 (2-5)

0.58 0.52 0.10 0.25 0.05 0.47 0.28 0.76 0.60 0.98 0.07 0.37 0.87 0.94 0.46 0.69 0.03 0.28

060 5.2 6 0.7 5 (2-6) 229.7 6 9.7

060 4.5 6 0.7 4.5 (1.5-5) 219.6 6 7.0

060 6.3 6 0.6 6 (5-7) 1.1 6 8.0*

1.0 0.25 0.29 0.04

Noninjured group

SCI-noNP group

* One way analysis of variance with Bonferroni post hoc test. Statistical significance at p , 0.05 are shown in italics. Pain-3 temperature rated at 7 s as 3/10 on the NRS. Parametric variables presented as mean 6 SE. Nonparametric data presented as median with the 25th-75th percentile range. CHEPs, contact heat evoked potentials; CPM, conditioned pain modulation; CPT, cold pain threshold; CS, conditioning stimulus; CT, cold detection threshold; EvHP, evoked heat pain; F, female; HADS, hospital anxiety and depression scale (A-anxiety, D-depression); HPT, heat pain threshold; M, male; NRS, numerical rating scale; PC-hs, pain catastrophizing helplessness score; QST, quantitative sensory testing; WT, warm detection thresholds.

heat pain intensity rated by the SCI-NP group (4.6 6 0.6 NRS units) was significantly higher than that experienced by the noninjured subjects (2.8 6 0.4 NRS units, P 5 0.03, Table 3). The unpleasantness of the tonic heat test stimulus was similar between experimental groups (P 5 0.28, Table 3). In the noninjured group, heat pain intensity at 10 seconds was rated as 3.5 6 0.3, which subsequently decreased to 2.8 6 0.4 at 20 seconds and 2.2 6 0.5 at 30 seconds, demonstrating significant habituation to tonic heat pain stimulation (10 seconds vs 30 seconds; P 5 0.003, Fig. 2A). In contrast, no habituation to tonic heat pain was revealed either in the SCI-noNP group (from 3.8 6 0.3 at 10 seconds to 3.6 6 0.5 at 30 seconds, Fig. 2A) or in the SCI-NP group (from 4.2 6 0.4 at 10 seconds to 4.9 6 0.8 at 30 seconds, Fig. 2A). Although no significant temporal summation of tonic heat pain intensity was observed in the SCI-NP group when compared with the 10–second pain intensity rating, these subjects reported higher values than the noninjured group at 20 seconds (P , 0.05; Bonferroni test) and at 30 seconds (P , 0.001; Bonferroni test). Two-way ANOVA highlighted a difference for mean pain intensity rated during the 12˚C CS when compared between groups (P 5 0.02; ANOVA) including time as a factor (P 5 0.002; ANOVA). However, the post hoc analysis failed to reveal specific differences between groups (P . 0.05; Bonferroni test). Maximal pain intensity rated during the 12˚C CS applied to the contralateral nondominant hand was higher than 5/10 NRS units for all groups (Fig. 2B), and a significant increase in pain intensity was experienced by all groups (P , 0.001, Fig. 2B). None of the groups experienced pain sensation during the 30-second hand immersion with the 33˚C CS (Table 3). Neither the N2/P2 amplitude (P 5 0.9) nor the CHEP habituation rate (P 5 0.9) was statistically different when compared between experimental groups (Table 3). Nevertheless, HPT measured

within the C6 dermatome negatively correlated with loss of CHEP habituation in the SCI-NP group (r 5 20.72; P 5 0.04, Fig. 2D), which was not identified in the SCI-noNP group (r 5 0.40; P 5 0.30, Fig. 2C). Finally, evaluation of EvHP assessed during repeated CHEP stimulation failed to reveal significant differences between groups measured either as pain intensity (P 5 0.9, Table 3) or as Cz/AFz habituation rate (P 5 0.5, Table 3). 4.3. Heterotopic CPM of tonic heat stimuli When tonic heat pain intensity was analyzed in the noninjured group immediately after the 33˚C or 12˚C CS compared with the rating made without CS, a general difference was identified between conditioning paradigms (P , 0.001; ANOVA, Fig. 3A), which reflected significant inhibition of pain perception at 10, 20, and 30 seconds after painful heterotopic stimulation (Bonferroni post hoc analysis) (Fig. 3A). A similar pattern of modulation of tonic heat pain intensity was identified in the SCI-noNP group when the response measured after the conditioning stimuli were compared together (P , 0.001; ANOVA), characterized as inhibition of pain perception at 10, 20, and 30 seconds after the 12˚C CS compared with the rating made without CS application or with 33˚C CS (Fig. 3B). In contrast, no significant modulation of tonic heat pain intensity was rated by the SCI-NP group immediately after application of the 12˚C CS (Fig. 3C), which was confirmed by the 2-way ANOVA analysis for the effect of the different CS paradigms compared together (P 5 0.9) or for the effect of time as a factor (P 5 0.8). A general difference of the effect of 12˚C CS on tonic heat pain intensity was evident when the experimental groups were compared together (P , 0.001, Fig. 3D) including time analyzed as a factor (P 5 0.02). Calculation of the mean CPM response, where the effect rated after 33˚C CS was subtracted from the 12˚C CS modulatory

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Figure 2. Tonic thermal pain intensity and contact heat evoked potential amplitude as measures of pain modulation. (A), Pain intensity rated during the individualized tonic heat stimulus revealed habituation in the noninjured group (30 seconds vs 10 seconds; ##P 5 0.003), which was not evident in the SCI groups. Tonic heat pain intensity increased in the SCI-NP group at 20 seconds (*P , 0.05) and 30 seconds (***P , 0.001) when compared with the noninjured group. (B), Pain intensity measured during the tonic 30-second 12˚C CS revealed a general increase rated by all experimental groups (30 seconds vs 10 seconds; P , 0.001). (C), HPT measured in the SCI-noNP group showed no relationship with Cz/AFz CHEP habituation rate. (D), In contrast, the SCI-NP group was characterized by a significant negative correlation between HPT and Cz/AFz CHEP habituation rate, indicating that lower HPT was related to low habituation of evoked potential amplitude. CHEP, contact heat evoked potential; HPT, Heat pain threshold; SCI, spinal cord injury; SCI-NP, spinal cord injury with neuropathic pain; SCI-noNP, spinal cord injury without neuropathic pain.

response, demonstrated a significant difference for this parameter when compared between groups (P , 0.001). The mean CPM response rated by the noninjured group (229.7% 6 9.7%, P 5 0.043) was greater than the response rated in the SCI-NP group (1.1% 6 8.0%, P 5 0.043, Table 3) but not in the SCInoNP group (219.6% 6 7.0%, P 5 0.27) after heterotopic 12˚C CS. Temporal analysis of the mean CPM response of tonic heat intensity also highlighted early inhibition of tonic heat pain induced by the 12˚C CS at 10 seconds for both the noninjured (P , 0.05) and SCI-noNP group (P , 0.05, Fig. 3D). Pain intensity associated with the 12˚C CS stimulus was not related to the magnitude of change in tonic test heat pain intensity in the noninjured (r 5 0.58; P 5 0.066), SCI-noNP (r 5 0.22; P 5 0.51), or SCI-NP group (r 5 0.14; P 5 0.068).

4.4. Relationship between basal Cz/AFz evoked potentials and EvHP intensity with the mean CPM response The mean CPM response rated by the SCI-NP group after 12˚C CS of the tonic heat pain demonstrated important correlations with CHEP amplitude and EvHP intensity (Fig. 4 and 5). Although no relationship was identified between the CHEP amplitude and the mean CPM response in the SCI-noNP group (r 5 0.30; P 5 0.38, Fig. 4C), a positive correlation was identified between these parameters in the SCI-NP group (r 5 0.80; P 5 0.02, Fig. 4D). Similarly, EvHP intensity associated with the contact heat stimuli failed to show a correlation with the mean CPM response in the SCI-noNP group (r 5 20.20; P 5 0.578, Fig. 5A) when compared with the positive relationship observed in the SCI-NP group (r 5 0.80; P 5 0.007, Fig. 5B).

The importance of assessing CPM of tonic heat pain stimuli was revealed when pain perception modulation was correlated with Cz/AFz CHEP amplitude or EvHP intensity in the SCI-NP group at 10, 20, or 30 seconds. The CPM response and EvHP intensity correlated at 10 seconds (0.76, P , 0.01), 30 seconds (0.85, P , 0.001), and for the mean 10 to 30 seconds (0.80, P 5 0.007). These data suggest that the relationship between the mean CPM response and basal measures of evoked potentials or EvHP can only reliably be revealed during the application of tonic heat pain stimuli, where the measures are pooled during the entire 30–second test stimulus period. Examination of the individual mean CPM response in both the SCI-noNP and SCI-NP groups revealed some subjects without efficient CPM or with deficient CPM of tonic heat pain intensity after 12˚C CS. After application of the 12˚C CS, both efficient CPM (SCI-noNP 5 7) and deficient CPM (SCI-noNP 5 1) were observed. Post hoc analysis of the Cz/AFz CHEP amplitude was performed to further define the difference between basal measures of thermal sensory function in subjects with SCI-NP exhibiting efficient or deficient CPM. As such, larger N2/P2 CHEP amplitude in the SCI-NP group was associated with deficient CPM (35.5 6 3.0 mV) compared with efficient CPM (24.05 6 2.2 mV, P 5 0.02; Mann–Whitney test). Finally, the WT assessed in the C6 dermatome was higher in the SCI-NP subgroup with deficient or no response to CPM (35.1 1/2 0.3˚C) when compared to the SCI-NP subgroup with intact inhibitory CPM (34.0 1/2 0.1˚C, p50.001, Mann-Whitney test). To control for the possible influence of outliers on the correlations presented in Figure 4 C and D and Figure 5 A and D, data greater than 1.5 to 2.0 of the SD of the mean value were excluded, so that the analysis could be repeated. No

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Figure 3. Conditioned pain modulation deficit demonstrated in subjects with SCI-NP during tonic heat stimulation. (A), Inhibition of tonic heat pain was induced after CPM with 30-second 12˚C stimulation at 10 seconds (***P , 0.001), 20 seconds (**P , 0.01), and 30 seconds (**P , 0.01) when compared with the response measured either without the conditioning stimulus (No CS), or to the effect observed after the 30-second 33˚C CS (33˚C CS) at 10 seconds (##P , 0.01), 20 seconds (#P , 0.05), or 30 seconds (#P , 0.05). (B), CPM with 12˚C CS was also revealed in the SCI-noNP group at 10 seconds (*P , 0.05), 20 seconds (*P , 0.05), and 30 seconds (*P , 0.05) when compared with the No-CS response, and at 10 seconds (#P , 0.05), 20 seconds (#P , 0.05), and 30 seconds (#P , 0.05) when compared at 33˚C CS. (C), No CPM of the tonic heat pain intensity was observed in the SCI-NP group after 12˚C CS, indicating deficient CPM. (D), Evaluation of mean CPM after 12˚C CS revealed significant inhibition of tonic heat pain intensity at 10 seconds, but not at 20 seconds or 30 seconds, in the noninjured group (*P 5 0.043) when compared with the SCI-NP group. CS, conditioning stimulus; CPM, conditioned pain modulation; SCI-NP, spinal cord injury with neuropathic pain; SCI-noNP, spinal cord injury without neuropathic pain.

outliers were identified in the SCI-NoNP group (Figs. 4C and 5A). In Figure 4D, 1 outlier was removed from original data set, without affecting the significant positive relationship identified between mean CPM response and Cz amplitude (r 5 0.67; P 5 0.049). Elimination of outliers in Figure 5B also failed to influence the positive relationship between mean CPM response and EvHP intensity (r 5 0.73; P 5 0.026).

4.5. Multiple linear regression with clinical measures of pain Based on the best subset and forward stepwise multiple regression analysis, tonic pain intensity, habituation, and CPM measures recorded in the SCI-NP group were found to predict clinical outcomes of pain assessed with the BPI and NPSI questionnaires (Table 4). The best subset analysis identified

Figure 4. Contact heat evoked potential amplitude correlates with mean CPM during SCI-NP. Typical individual and averaged Cz/AFz CHEPs recorded from subjects in the SCI-NP group who demonstrated either (A) efficient (subject #20) or (B) deficient (subject #5) mean 10- to 30-second CPM response. (C), In the SCInoNP group, no relationship was revealed between mean Cz/AFz N2/P2 CHEP amplitude and mean 10- to 30-second CPM. (D), In contrast, a significant positive correlation was identified between Cz/AFz N2/P2 CHEP amplitude and the mean 10- to 30-second CPM response in the SCI-NP group, suggesting that the development of deficient CPM during NP was associated with larger evoked potentials. CHEPs, contact heat evoked potentials; CPM, conditioned pain modulation; SCI-NP, spinal cord injury with neuropathic pain; SCI-noNP, spinal cord injury without neuropathic pain.

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Figure 5. Contact heat evoked pain intensity correlates with mean CPM. (A), In the SCI-noNP group, no relationship was identified between mean EvHP intensity rated during 10 consecutive contact heat evoked stimuli and the mean 10- to 30-second CPM response. (B), In contrast, a positive correlation was identified between EvHP intensity and the mean 10- to 30-second CPM response in the SCI-NP, indicating that the development of deficient CPM was related to the perception of higher heat-evoked pain intensity. CPM, conditioned pain modulation; EvHP, evoked heat pain; SCI-NP, spinal cord injury with neuropathic pain; SCI-noNP, spinal cord injury without neuropathic pain.

a contribution from tonic pain, habituation, and CPM measures to the BPI pain severity (R2 5 0.97) and NPSI burning spontaneous pain (R2 5 1.00), pressing spontaneous pain (R2 5 0.72), and paroxysmal pain subscores (R2 5 0.90). However, the forward stepwise regression analysis specifically identified mean 12˚C CS pain intensity, habituation rate of EvHP intensity and the mean CPM response together as the strongest predictors of the BPI pain severity (R2 5 0.84, a 5 0.99) and of the NPSI burning spontaneous pain subscore (R2 5 0.72, a 5 0.91).

5. Discussion This study demonstrates deficient CPM in subjects with SCI-NP compared with individuals without pain or with the noninjured control group. Significant temporal summation of pain intensity was not characteristic of SCI-NP at the test site. Less-efficient CPM correlated significantly with pain severity and pressing

(deep) spontaneous pain as measured with the BPI and NPSI questionnaires, respectively. Although no significant difference was observed for basal measures of heat pain threshold or Cz/AFz CHEPs between subjects with or without NP, these measures also correlated significantly with deficient CPM in subjects with SCI-NP.

5.1. SCI-NP, habituation, and temporal summation to tonic heat pain Significant loss of habituation to tonic heat pain was reported by subjects with SCI-NP compared with the noninjured group, through the entire 30–second test period. However, loss of habituation was also observed in the SCI-noNP group. In an effort to identify mechanisms of change in central processing to pain stimuli,38 repeated or prolonged exposure to noxious stimuli have demonstrated reduced habitation to test stimuli.15,25,47,50,56 Specific loss of habituation in subjects with SCI-NP has also

Table 4

Multiple linear regression factor analysis for tonic pain, habituation and CPM with the BPI and NPSI subscores for subjects with SCI and NP. Factor Tonic pain stimuli Pain-3, ˚C Mean pain-3 tonic test heat pain INT (0-10, NRS) Mean pain-3 tonic test heat pain unpleasantness (0-10, NRS) Mean 12˚C CS INT (0-10, NRS) Mean 12˚C CS unpleasantness (0-10, NRS) Habituation EvHP habituation rate, % CHEP habituation rate (%) CPM Mean 10-30 s CPM, % Best subset regression R2 Stepwise forward regression R2 Power (alpha)

BPI subscore

NPSI subscore

SEV (0-40)

INT (0-80)

BSP (0-10)

PSP (0-10)

PP (0-10)

EP (0-10)

PD (0-10)

P 5 0.179* E.

P 5 0.060*† E.

P 5 0.027* P 5 0.043*

E. E.

E. E.

P 5 0.063*† E.

P 5 0.197* E.

P 5 0.011*

E.

P 5 0.011*

E.

E.

E.

E.

P 5 0.029*† P 5 0.014*

E. E.

P 5 0.016* P 5 0.012*

E. E.

P 5 0.116* E.

E. E.

E. E.

P 5 0.006† P 5 0.091*

E. E.

P 5 0.013* P 5 0.017*

P 5 0.052*† E.

P 5 0.009* P 5 0.075*

E. E.

E. E.

P 5 0.021*† 0.97 0.84 0.99

E. 0.38 0.38 0.47

P 5 0.036* 1.00 E. –

P 5 0.006*† 0.72 0.72 0.91

P 5 0.002* 0.90 E. –

E. 0.37 0.37 0.46

E. 0.20 E. –

* Best subset multiple regression. † Forward stepwise multiple regression. BPI, brief pain inventory; BSP, burning (superficial) spontaneous pain; CHEP, contact heat evoked potential; CPM, conditioned pain modulation; CS, conditioning stimulus; E., excluded from forward stepwise regression analysis; EP, evoked pain; EvHP, evoked heat pain; INT, pain interference; NRS, numerical rating scale; NPSI, Neuropathic Pain Symptom Inventory; Pain-3, temperature rated at 7 s as 3/10 on the NRS; PD, paresthesia/dysesthesia; PP, paroxysmal pain; PSP, pressing (deep) spontaneous pain; R2, multiple linear adjusted regression; SEV, pain severity.

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been identified using repeated CHEP analysis.40 Habituation measured in response to heat stimuli is mainly mediated by peripheral mechanisms, including peripheral nociceptor fatigability.1,27 Other studies using psychophysical and functional magnetic resonance imaging techniques have demonstrated that both temporal summation69,72 and habituation51 can be measured at the cortical and subcortical level in healthy subjects.75,81 Although loss of habituation to tonic heat pain in the SCI-NP group may reflect a loss of peripherally mediated habituation and an increase in central facilitation,75,81 further studies should assess whether loss of this specific EPM mechanism is characteristic of this population of subjects.

5.2. SCI-NP and CPM of tonic heat pain A complete loss of efficient CPM was observed in the SCI-NP group compared with either the noninjured control group or subjects without pain after SCI, as demonstrated by measuring inhibition of tonic heat pain after heterotopic noxious conditioning stimulation. Loss of efficient CPM in subjects with chronic pain has been identified in a range of pathologies44,67,85 and in subjects with NP and altered nociception.80 Closer examination of individual mean CPM response scores also revealed a subgroup of subjects with SCI-NP that developed deficient CPM, which has also been observed in subjects with irritable bowel syndrome.83 Several spinal and supraspinal mechanisms may mediate loss of efficient CPM in SCI-NP. At the spinal level, dysfunction of propriospinal circuits9,61 may contribute to altered CPM in subjects with SCI-NP.57 At the supraspinal level, several structures have been implicated in CPM,67 including the mesencephalic pontine reticular formation and anterior thalami.42 In SCI-NP, the metabolic status of the anterior cingulate and prefrontal cortex is altered,66,81 particularly in individuals with a high degree of affective distress and pain intensity.81 Interestingly, these centers also play a role in habituation65 and CPM,16,19,49 suggesting that their common role in EPM dysfunction should be examined.

5.3. Basal sensory correlates of EPM dysfunction in subjects with SCI-NP Our study failed to demonstrate lower HPTs above the level of the SCI in subjects with NP, in line with the observations of other studies.14,20,87 However, this study supports the application of heat pain test stimuli to reveal psychophysical measures of EPM deficit in subjects with SCI-NP. Heat pain stimuli have been used to study EPM processes such as habituation,27,40,53 temporal summation,68,69 and CPM.35,48 Although no difference in EvHP intensity or Cz amplitude was identified between the SCI groups with or without NP, a strong association between Cz/AFz CHEPevoked potential amplitude and deficient mean CPM was identified in the NP group.29 Closer examination of the relationship between basal measures of QST or neurophysiological measures of cortical excitability to noxious heat stimuli tested above the injury level may provide additional diagnostic value for the identification of EPM dysfunction in subjects NP.3 5.4. Factors that affect measurement of EPM deficit in subjects with SCI-NP Several factors have been identified that may influence assessment of the EPM system, including the test and conditioning

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stimuli, and perceived pain intensity.31,44,62,75,79,80 Importantly, in this study, the deficient CPM was unrelated to the conditioning pain stimulus intensity.26,41 However, in this study the choice of the specific tonic heat pain test and conditioning stimuli may have introduced methodological errors associated with the measurement of EPM dysfunction during NP.10,43,55 There is a need to control the level of perceived pain and the test stimulus temperature because these factors may affect the measured direction of habituation and sensitization with tonic pain test stimuli.79 In this study application of the pain-3 tonic heat test stimulus was well tolerated up to 30 seconds and the pain intensity was relatively low in all experimental groups. Therefore, the selection of these specific parameters in this study may have been instrumental in revealing loss of habituation and efficient CPM for the first time in subjects with SCI-NP.

5.5. Clinical relevance and study limitations Although a lower heat pain threshold has been identified above the level of SCI in subjects with NP,40 this sensory deficit was not diagnosed in other studies,14,20,87 including our own study. Indeed, this study revealed no difference in heat pain threshold, EvHP intensity, or Cz/AFz evoked potential amplitude between experimental groups. Nevertheless, heat pain threshold and noxious-CHEP amplitude correlated significantly with EPM dysfunction in the SCI-NP group in this study.3 The strong relationship identified between the mean CPM response measures with the clinical subscores of the BPI and NPSI questionnaires supports the hypothesis that measurement of EPM dysfunction could have potential diagnostic value, especially with regard to understanding general pain severity (BPI) and pressing (deep) spontaneous pain (NPSI, Table 4). Furthermore, examination of EPM dysfunction in subjects with SCI-NP may have greater diagnostic utility than QST measures alone,28 including prognostic value with regards to examining treatment efficacy.84-86 The correlation of deficient CPM with the clinical pain subscores indirectly supports the consistency and robustness of this measure of NP in this patient population (Table 4). Psychophysical rating of the deficient CPM response in the SCINP group is strongly associated with 2 clinical spontaneous pain measures assessed with 2 pain questionnaires. Furthermore, the best subset multiple regression analysis (Table 4) clearly demonstrates that mean CPM response in the SCI-NP group significantly contributes to different pain symptoms such as burning spontaneous pain, pressing spontaneous pain, and paroxysmal pain. Future neurophysiological studies should assess the nature of the relationship between evoked Cz potential amplitude as a measure of habituation and CPM dysfunction, compared with the psychophysical metrics performed on subjects with SCI-NP. It is important to emphasize that the reported results were obtained from a relatively small group size of 10 patients for each of the SCI cohorts (c.f. Ref. 55). Nevertheless, the statistical power associated with the results approximated 0.8 in the noninjured group for inhibition of the pain-3 intensity after application of the 12˚C CS (0.76, Fig. 3A). Another possible limitation of this study is the early time (6.5 months) at which the subjects were examined after SCI. Although the development of at-level and below-level SCI-NP may have different temporal profile, at-level pain develops early after injury (1-2 months) and could contribute equally to the psychosocial impact at this time.71 Furthermore, at-level SCI-NP may be mediated by a combination of peripheral and central

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mechanisms of SCI-NP.22,77 Therefore, a longitudinal study to identify increased temporal summation, loss of habituation, or lessefficient CPM would be of interest not only to establish the relationship between EPM dysfunction and the chronicity of belowlevel SCI-NP (central pain) but also with respect to predicting the development of debilitating chronic NP symptoms. Finally, the contribution of the subject’s medication and its influence on EPM in the SCI-NP group was not controlled.36,45,52 The opioid oxycodone is known to alter temporal summation, but not CPM in healthy volunteers,70 whereas a dopamine agonist has recently been shown to increase CPM.74 In our study, the effect of antiepileptics, such as pregabalin, on CPM was not assessed. However, it is important to note that in a study of chronic pancreatitis, subjects failed to rate the effect of pregabalin on CPM,7 suggesting that the influence of this first-line medication for SCI-NP may not affect this specific mechanism of EPM.

6. Conclusions Efficient EPM has been shown to be degraded in subjects with SCI-NP, when assessed above the injury level as deficient CPM of tonic heat pain, and that this measure contributes to clinical measures of spontaneous pain. The diagnosis of deficient conditioned pain modulation during the application of tonic heat pain test stimuli should further contribute to our understanding of both spinal and supraspinal pathophysiological sensory mechanisms of NP after SCI.23,24

Conflict of interest statement The authors have no conflicts of interest to declare. This work was supported by the European “Fondos FEDER,” “Fundacion ´ Mutua Madrilen˜a 2010 and 2013,” Pfizer Liira (Investigator Initiated) project, “Consolider-Ingenio 2010 Hyper” project from the “Ministerio Ciencia e Innovacion” ´ (CSDOOC-09-61313 to E.B.E.), and the “CERES” project from the “Centro para el Desarrollo Tecnologico ´ Industrial CDTI.” The funding sources had no such involvement in this study. The NPSI was provided to Dr Taylor by Pfizer as part of the Liira project.

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The authors thank the subjects for participating in this study and the support of the hospital staff.

[19]

Article history: Received 24 July 2014 Received in revised form 7 November 2014 Accepted 13 November 2014

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