Research Paper

Distinct quantitative sensory testing profiles in nonspecific chronic back pain subjects with and without psychological trauma Jonas Tesarza,*, Andreas Gerhardta, Sabine Leisnera, Susanne Jankea, Rolf-Detlef Treedeb, Wolfgang Eicha

Abstract Psychological trauma is associated with an increased risk for chronification of nonspecific chronic back pain (nsCLBP) independent of posttraumatic stress disorder (PTSD). However, the mechanisms underlying the role of psychological trauma in nsCLBP are less clear than in PTSD. Therefore, this study considered whether psychological trauma exposure (TE) is accompanied by specific alterations in pain perception. The study included 56 participants with nsCLBP and TE (nsCLBP-TE), 93 participants with nsCLBP without TE (nsCLBP-W-TE), and 31 pain-free controls. All participants underwent a thorough clinical evaluation. The standardized quantitative sensory testing protocol of the “German Research Network on Neuropathic Pain” was used to obtain comprehensive profiles on somatosensory functions in painful (back) and non-painful areas (hand). The protocol consisted of thermal and mechanical detection as well as pain thresholds, vibration thresholds, and pain sensitivity to sharp and blunt mechanical stimuli. Psychological trauma was validated by structured clinical interview. Trauma-associated symptom severity, anxiety, and depressive symptomatology were assessed by self-report questionnaires. Differences in somatosensory function were seen only for pressure pain thresholds. Compared with controls, nsCLBP-TE revealed hyperalgesia generalized in space with lower thresholds in painful and non-painful areas, whereas nsCLBP-W-TE demonstrated localized alterations with decreased thresholds only in the painaffected area of the back (P # 0.006). Our findings suggest an augmented central pain processing in nsCLBP-TE (alterations in painful and non-painful areas), whereas nsCLBP-W-TE show only local changes (alterations only in the painful area) suggesting regional sensitization processes. This finding might explain why TE without PTSD is associated with an increased prevalence of chronic pain. Keywords: Chronic back pain, Psychological trauma, Pain perception, Pressure pain threshold, Quantitative sensory testing

1. Introduction Chronic low back pain (CLBP) is one of the most common causes of morbidity and is of enormous socioeconomic relevance.28,33 However, all of the known anatomic factors that might cause CLBP have not been able to fully explain the symptoms in a significant number of subjects.9,35 Therefore, these individuals are commonly referred to as having “nonspecific” CLBP (nsCLBP). This does presume that specific pathologies have been ruled out following a clinical assessment that includes appropriate tests and imaging.3,14,18 Thus, there is often a mismatch between objective anatomic and physiological findings and symptoms.13,49 This mismatch has led to studies of the psychosocial factors that may contribute to nsCLBP. However,

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a

Department of General Internal Medicine and Psychosomatics, Medical Hospital, University of Heidelberg, Heidelberg, Germany, b Department of Neurophysiology, Centre for Biomedicine and Medical Technology Mannheim (CBTM), University of Heidelberg, Heidelberg, Germany *Corresponding author. Address: Department of General Internal Medicine and Psychosomatics, Medical Hospital, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. Tel.: 149 6221 56 37862; fax: 149 6221 56 5749. E-mail address: [email protected] (J. Tesarz). PAIN 156 (2015) 577–586 © 2015 International Association for the Study of Pain http://dx.doi.org/10.1097/01.j.pain.0000460350.30707.8d

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one important issue that the existing studies have neglected is the role of psychological trauma. Chronic low back pain and psychological trauma are two closely associated conditions.41,56 More significantly, psychological trauma is associated with an increased risk of developing nsCLBP.42,48 Despite this association, the neurobehavioral mechanisms underlying this phenomenon are incompletely understood. Only recently have researchers started to investigate these mechanisms using experimental models, and subsequently, evidence of pain alterations in trauma-exposed individuals has been demonstrated.40 However, the findings of the few studies examining pain responses in individuals with exposure to psychologically traumatic events (trauma exposure [TE]) and posttraumatic stress disorder (PTSD) are inconsistent, with results pointing to both increased11,43 and decreased11,20,32 pain sensitivity. Results indicating no alterations have also been found.47 This ambiguity may be because different pain induction methods with nonstandardized and nonvalidated testing paradigms were used. Additionally, experimental studies were usually limited to single pain induction method, instead of using a comprehensive quantitative sensory testing (QST) protocol. The situation is further complicated by the fact that the research on pain perception to date has tended to focus on painfree PTSD subjects only, neglecting both the role of TE alone without the development of a full PTSD symptomatology and the significance of TE in chronic pain patients. Evidence shows that regardless of the presence or absence of PTSD, TE is an www.painjournalonline.com

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important predictor of chronic pain.22,36 Concerning underlying mechanisms, however, the role of TE is less clear. Trauma-exposed subjects without PTSD have been compared with healthy controls in only 2 studies. These demonstrated that in trauma-exposed women, TE, but not PTSD, may have explained the differences observed in pain unpleasantness.23 Consistent with that, significantly different pain thresholds in combat subjects who did not develop PTSD compared with a healthy control sample were reported.32 Nonetheless, that study included only 10 subjects per group, and none of the 2 studies addressed pain patients. Therefore, studies including trauma-exposed pain subjects without PTSD are important, as TE may lead to pain alterations by mechanisms different from those of PTSD. Because of the inconsistent findings of the previous research, this study was explorative. No specific hypothesis was stated. Therefore, the aim of this study was to examine descriptively whether TE may lead to differences in pain perception in nsCLBP using a standardized and validated QST protocol.

2. Methods This study is part of the research consortium “Localized and Generalized Musculoskeletal Pain: Psychobiological Mechanisms and Implications for Treatment” (“LOGIN,” subproject number 6: “Subgroups characterized by psychological trauma, mental comorbidity, and psychobiological patterns and their specialized treatment”) and funded by the German Federal Ministry of Education and Research (01EC1010A-F). More details concerning LOGIN can be found elsewhere.19,37 All participants provided written informed consent before inclusion in the study. The study was approved by the Ethics Research Committee of the Faculty of Medicine, University of Heidelberg (S-261/2010), and was conducted in compliance with the Helsinki Declaration. 2.1. Study design In this study, 149 subjects with nsCLBP and 31 pain-free controls were included. Inclusion criteria were as follows: presence of nsCLBP lasting for $45 days during the past 3 months, at least 18 years of age, and fluent German language skills. Controls were ageand gender-matched and did not report any history of chronic or current pain. To achieve optimal representativeness of the controls compared with the “overall nsCLBP group,” control subjects were included irrespective of the existence of any traumatic event or not. Participants were advised not to take any medication 24 hours before the investigation. The exclusion criteria were: specific pathologies of CLBP (eg, structural findings such as spinal canal stenosis, disc herniation, spondylolisthesis, infection, malignancy, rheumatic and systematic inflammatory disorders, and fracture), pain intensity of leg pain equal or higher than the intensity of back pain (sciatica pain), diseases affecting sensory processing (eg, diabetes, alcohol or substance abuse, neuropathy, inflammatory diseases), pain or surgery at the dorsum of the hand or back surgery in the past 3 years (because the hand and back were to be subjected to investigation), presence of PTSD, and cognitive impairment. All subjects underwent a thorough clinical evaluation by a physician including physical examination and structured clinical interview for DSM-IV (Diagnostic and Statistical Manual of Mental disorders, Fourth Edition) Axis I disorders (SCID). The clinical diagnosis of nsCLBP was validated during the clinical evaluation. A broad diagnostic investigation including physical examination, blood tests, and, if indicated, further technical investigations (x-ray, magnetic resonance imaging) was performed to rule out specific pathologies of CLBP.

Testing took place in a quiet room with temperature maintained at 22˚C 6 2˚C. Before starting the tests, the participants rested for half an hour in their respective environments. After filling in the questionnaires, the test procedure started with the QST protocol. An independent assessor who was not informed about the study aims and group memberships (nsCLBP or pain-free controls) conducted all assessments. 2.2. Sociodemographic variables Age, sex, marital status, level of education, and employment status were captured by questionnaire. Body mass index was calculated based on physical measurement of height and weight. For more details, see Table 1. 2.3. Psychological assessment To screen for and assess the presence of psychological trauma, a structured clinical interview (SCID) was administered to all participants. The German version of the SCID is a comprehensive, highly reliable, and valid instrument.52 Trauma exposure was assessed by the SCID regardless of the presence of the whole symptomatology of PTSD. Participants who positively answered at least 1 trauma item (“A1-criterion” for PTSD in the SCID: “The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others”) and fulfilled the criteria of a traumatic experience (“A2-criterion” for PTSD in the SCID: “The person’s response to the event must involve intense fear, helplessness, or horror”) were classified as participants with nsCLBP and TE (nsCLBP-TE). The remaining nsCLBP participants were classified as participants with nsCLBP without TE (nsCLBP-W-TE). The type of TE was classified according to the SCID trauma checklist and included the following list of events: serious accident, witnessing of traumatic event, violent assault, natural disaster, sexual assault, sexual contact when less than 14 years of age by someone more than 5 years older, and a residual category (“other types of traumatic exposure”). In addition to the diagnostic interview, all participants were administered the following additional measures to determine psychological symptom severity. 2.3.1. Posttraumatic Diagnostic Scale Severity of trauma-associated symptoms was assessed with the German version of the Posttraumatic Diagnostic Scale (PDS-D15). The PDS-D symptom severity score includes 17 items and is widely used for the assessment of posttraumatic symptom severity. Each item corresponds to one of the PTSD symptoms specified in DSM-IV, and ratings range from 0 (“never”) to 3 (“5 times per week or more/very severe/nearly always”). The PDS-D assesses the frequency of current PTSD symptoms in the past 4 weeks related to the most stressful life event. For analysis, we used the PDS-D sum score (range, 0-54) to estimate the severity of trauma-associated symptoms. The PDS-D has good reliability and high validity.24 High validity was also confirmed in our study with Cronbach’s a 5 0.92. 2.3.2. Hospital Anxiety and Depression Scale The Hospital Anxiety and Depression Scale (HADS-D) was used to determine the severity of anxiety and depressive symptoms. The HADS is a 14-item self-assessment scale for measuring distress with 2 subscales for anxiety and depression. Each scale consists of 7 items that measure anxiety and depression through the patient’s self-report with a 4-stage response format. Each HADS subscale

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Table 1

Sociodemographic characteristics and pain assessment. No. of subjects Age, mean (95% CI) Female sex, % Body mass index, mean (95% CI) Partnership (firm relationship), % Education (. 10 y in school), % Working status, % Employed Unemployed Retired Others Pain assessment CLBP intensity (NRS 0-10), mean (95% CI) Pain quality (SES), mean (95% CI) Affective pain experience (10-40) Sensory pain experience (14-56) History of CLBP, % ,1 y 1-10 y .10 y No. of painful areas (0-10), mean (95% CI) Functional back capacity (FFbH-R: 0-100), mean (95% CI) Health-related quality of life (SF-12), mean (95% CI) Physical component (0-100) Mental component (0-100) Pain medication, % Psychological assessment, mean (95% CI) Trauma symptom severity (PDS-D: 0-54) Anxiety (HADS: 0-21) Depression (HADS: 0-21)

nsCLBP-TE

nsCLBP-W-TE

Controls pain-free

56 55.8 (53.1; 58.6) 74.5 29.0 (27.2; 30.9) 78.2 23.6

93 58.2 (56.3; 60.2) 65.6 28.2 (26.9; 29.5) 79.6 33.3

31 60.1 (55.7; 64.5) 58.1 26.8 (25.3; 28.2) 70.1 41.9

41.8 3.6 45.5 9.1

40.9 8.6 43.0 7.5

48.4 3.2 38.7 9.7

5.4 (4.9; 6.0)

5.0 (4.5; 5.4)

28.9 (26.1; 31.6) 19.6 (17.7; 21.5)W

F/x2

P

1.898 2.640 1.378 1.089 3.272 2.387

0.153 0.273 0.255 0.598 0.189 0.894

-

1.870

0.174

26.0 (24.1; 28.0) 17.0 (15.7; 18.3)T

-

3.013 5.049 2.529

0.085 0.026 0.310

0 34.5 65.5 7.0 (6.4; 7.6)W 70.5 (64.3; 76.7)C

4.3 38.7 57.0 6.1 (5.6; 6.7)T 73.8 (69.8; 77.8)C

94.4 (93.7; 99.1)T,W

4.169 20.161

0.043 ,0.001

36.5 (33.7; 39.3)C 43.5 (40.5; 46.5)C 56.4W

38.5 (36.3; 40.6)C 45.8 (43.2; 48.4)C 37.6T

54.7 (53.5; 55.8)T,W 53.3 (51.5; 55.1)T,W -

39.547 7.712 4.908

,0.001 0.001 0.040

9.2 8.7 (7.7; 9.7)W,C 7.4 (6.2; 8.5)C

6.8 (5.9; 7.6)T,C 6.2 (5.2; 7.1)C

4.1 (3.2; 5.0)T,W 3.2 (3.2; 5.0)T,W

13.640 9.062

,0.001 ,0.001

P value calculated by 1-way ANOVA for continuous variables and by Fisher exact test for categorical variables; LSD for post hoc tests, if appropriate (C, significantly different compared with controls; T, significantly different compared with participants with nsCLBP-TE; W, significantly different compared with participants with nsCLBP-W-TE). F, test statistic; health-related quality: higher scores indicating better health status. nsCLBP, nonspecific chronic low back pain; nsCLBP-TE, nsCLBP with experienced psychological traumatic event; nsCLBP-W-TE, nsCLBP without experienced psychological traumatic event; CI, confidence interval; NRS, numerical rating scale; SES, Pain Experience Scale; FFbH-R, Hannover Functional Ability Questionnaire; SF-12, Short Form-12; PDS-D, Posttraumatic Diagnostic Scale; HADS, Hospital Anxiety and Depression Scale (higher scores indicating higher burden); ANOVA, analysis of variance; LSD, least significant difference.

ranges from 0 to 21,26 with scores of 10 or above considered to indicate conspicuous symptom severity levels. The HADS-D was especially developed for patients with somatic diseases and thus excludes physical symptoms that could be confounded with pain symptoms. The HADS-D has good reliability and high validity.26 Reliability in our study was Cronbach’s a 5 0.90 and a 5 0.84 for the depression and anxiety subscales, respectively. 2.4. Pain assessment Participants were instructed to rate their “chronic pain sensations” over the past 4 weeks before testing in regard to pain intensity, pain location, and spatial extent of pain, as well as pain quality including affective and sensory dimensions of pain. 2.4.1. Pain intensity Pain intensity is defined as how much a person hurts. It was assessed using a numerical rating scale (NRS), ranging from 0 “no pain” to 10 “worst pain imaginable.” 2.4.2. Number of painful areas Based on pain drawings (a sketched illustration of the body in front and back views), the number of painful areas was assessed using a 10-body section method (pain drawing was divided into

10 areas: head, neck, upper back, lower back, sternum, abdomen, left leg, right leg, left arm, right arm; the number of painful areas was used as a numeric measure of the spatial extent of pain). Therefore, each participant was asked to complete a body pain diagram, marking all areas where pain was experienced. To ensure that the patients focus not only on back pain, the instructions stated, “Mark all areas where you experience pain (That is all the affected areas, not only the back!). Mark the total area where pain is experienced.” Afterward, the pain diagram was discussed jointly by the participant and the physician to rule out any misunderstandings. Based on the assessment of the pain drawings, participants were classified as “chronic widespread pain” (defined as pain that simultaneously exists as axial pain, upper and lower segment pain, and left- and right-sided pain) and chronic local pain (chronic widespread pain criteria not fulfilled) according to the American College of Rheumatology criteria.53 2.4.3. Pain quality Pain quality referred to the specific physical sensations associated with pain. The affective and sensory dimensions of pain were measured using the Pain Experience Scale (SES: “Schmerzempfindungs-Skala”). The SES is the standard instrument of the German chapter of the International Association for the Study of Pain. The SES consists of 10 items on a sensory

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subscale (eg, “throbbing,” “wrenching,” or “stinging”) and 14 items on an affective subscale (eg, “exhausting,” “fearful,” or “unbearable”). The response format is a 4-stage format (1: “not appropriate,” 2: “somewhat appropriate,” 3: “generally appropriate,” 4: “fully appropriate”). The sensory score of the SES is the mean of all sensory items (range, 14-56); the affective score of the SES is the mean of all affective items (range, 10-40). The SES has good reliability and high validity.17 Excellent reliability was confirmed in our study. Cronbach’s a for the affective subscale was 0.95 and for the sensory subscale was 0.91. 2.4.4. Functional back capacity Functional back capacity was assessed with the Hannover Functional Ability Questionnaire for measuring back pain–related disability (FFbH-R).30 The FFbH-R measures pain-related functional disability caused by back pain. It consists of 12 self-administered items that focus on daily activities that are restricted by musculoskeletal disorders (eg, putting on socks, sitting on a hard chair, and lifting). The response format is in 3 stages (“yes,” “yes with trouble,” and “no or with the help of another person”). The answers were transformed into a functional ability score that ranged from 0% to 100% (80%-100%: “no functional disability,” approximately 70%: “moderate disability,” and ,60%: “relevant disability”). The results from different studies indicate that the FFbH-R meets relevant psychometric criteria and is sensitive to change.30,39 The FFbH-R showed good reliability in our sample (Cronbach’s a 5 0.92). 2.4.5. Health-related quality of life Health-related quality of life was measured by the 12-item Short Form Health Survey (SF-12).50 The SF-12 permits the summation of individual items to yield both mental component summary score and physical component summary score. Separate summary scores were obtained for each of the physical and mental domains by summing the respective items for each score. The mental component summary score and the physical component summary score are norm-based with a mean and SD of 50 6 10 and range from 0 to 100 with higher scores indicating better health status. The SF-12 has been validated in patients with pain and is characterized by good reliability (Cronbach’s a $ 0.75 for the mental component summary scale and $0.82 for the physical component summary scale, respectively) and high validity. 2.5. Quantitative sensory testing protocol Somatosensory function was assessed using the comprehensive QST protocol, which was developed as part of the German Research Network on Neuropathic Pain (DFNS).45 It covers all relevant aspects of the somatosensory system, including large and small fiber functions, and signs of central sensitization. In this manner, detailed profiles of somatosensory function for the tested body areas were obtained. Test areas were distributed throughout the paraspinal muscles at the height of lumbar segments L1 to L5 of the low back area (5 6 0.5 cm next to the midline on the autochthonous back muscles) and on the dorsum of the ipsilateral hand. Test sides (right vs left) were determined in a randomized order. To familiarize participants with the test procedure, all tests were first conducted over an area that was not tested later during the QST session. 2.5.1. Thermal detection and thermal pain thresholds The tests for thermal detection thresholds (warm detection threshold [WDT] and cold detection threshold [CDT]), thermal

pain thresholds (heat pain threshold [HPT] and cold pain threshold [CPT]), and paradoxical heat sensations (PHS) were conducted using a TSA 2001-II (Medoc, Israel) thermal sensory testing device.55 All thermal thresholds (WDT, CDT, heat pain threshold, cold pain threshold) were obtained using ramped stimuli (1˚C/s, 32˚C baseline, 0˚C and 50˚C cutoffs, 9-cm2 thermode), which were terminated when participants pressed a button. The mean of 3 consecutive measurements was calculated. For the test procedure of the thermal sensory limen (TSL), including a test of the presence of PHS, subjects were asked to press a stop button as soon as they perceived a change of temperature toward warm or cool and to indicate verbally whether they felt warm or cool. Temperature changed after each press of the stop button toward the opposite direction without a rest at baseline temperature, leading to 6 stimulations alternating toward warm and cold. For TSL, values were indicated as mean difference between temperature for warm and cool perception. Paradoxical heat sensations were counted if subjects indicated a sensation of warmth, heat, or burning pain upon cooling stimuli, with a maximal number of 3 per test. 2.5.2. Mechanical detection threshold The mechanical detection threshold (MDT) was measured with a standardized set of modified von Frey filaments (Optihair2-Set; Marstock Nervetest, Schriesheim, Germany) that exert forces between 0.25 and 256 mN.16 The contact area was of uniform size and shape (round, 0.5 mm in diameter). Using the “method of limits,” 5 threshold determinations were made, each with a series of ascending and descending stimulus intensities.4 The final threshold was the geometric mean of these 5 series of ascending and descending stimulus intensities. 2.5.3. Mechanical pain threshold The mechanical pain threshold (MPT) was measured using a set of weighted pinprick stimulators (ThePinPrick; MRC, Heidelberg, Germany) with a flat contact area of 0.25 mm diameter that exert forces between 8 and 512 mN.4 Again, using the method of limits, the threshold was the geometric mean of 5 series of ascending and descending stimulus intensities. 2.5.4. Mechanical pain sensitivity including dynamic mechanical allodynia A total of 50 stimuli, 15 tactile (brush, cotton wool, and Q-tip) and 35 pinprick, were delivered. These stimuli were given in runs of 10 (5 runs per test site), and each run consisted of a different pseudorandom sequence of 3 tactile and 7 pinprick stimuli. All stimuli were applied with a 10-second interstimulus interval, well below the critical frequency for wind-up. The participant was asked to rate each stimulus for pain on a 0 to 100 NRS (0 indicating “no pain” and 100 indicating “most intense pain imaginable”). The mechanical pain sensitivity (MPS) was determined using the same weighted pinprick stimuli as that for MPT. To obtain stimulus response function, these 7 pinpricks were applied in a balanced order 5 times each. The geometric mean of the 35 pain ratings was the final value for MPS. The dynamic mechanical allodynia (DMA) was determined using a set of 3 light tactile stimulators.4,34 They were intermingled with the pinprick stimuli in a balanced order (each 5 times). The geometric mean of the 15 pain ratings (across all 3 different types of light touch stimulators) was the final value for DMA.

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2.5.5. Wind-up ratio In this test of temporal summation, the perceived magnitude of a single pinprick stimulus was compared with that of a train of 10 pinprick stimuli of the same force (256 mN) repeated at a 1 per second rate over the same body area. Between the single stimulus and the 10 pinprick stimuli, there was a break of 10 seconds. The procedure was repeated 5 times at different skin sites within the same body region. The train of pinprick stimuli was given within a small area of 1 cm2, and the subject was asked to give a pain rating representing the pain at the end of the train using a NRS. The mean ratings of series divided by the mean pain ratings of single stimuli was calculated as wind-up ratio (WUR). 2.5.6. Pressure pain threshold The pressure pain threshold (PPT) was measured over muscle (paraspinal muscles, thenar eminence) using an Algometer (Wagner Instruments, Riverside, CT) with a probe diameter of 1.0 cm that exerts pressure up to 20 kg. The PPT is determined by 3 ramped stimuli each applied with a slope of 0.5 kg/s. Pressure pain threshold was the mean of the 3 consecutive measures. 2.5.7. Vibration detection threshold The vibration detection threshold (VDT) was determined with a Rydel-Seiffer tuning fork (64 Hz, 8/8 scale), which was placed over the bony prominence of the tested body area (spinous process of the fourth lumbar vertebrae and processus styloideus radii, respectively) 3 times. Subjects indicated the time when they no longer experienced vibratory sensations. Vibration detection threshold was the mean of the 3 measures. 2.6. Statistical analysis All analyses were conducted using SPSS for Windows 21.0 software (SPSS, Inc, Chicago, IL). Descriptive statistics are presented as the means and SDs for continuous variables and absolute numbers and percentages for categorical variables. To determine whether there are significant group differences between nsCLBP-TE, nsCLBP-W-TE, and pain-free controls, analysis of variance (ANOVA) was used, followed by least significant difference test, if appropriate. In addition, The Kruskal–Wallis Test and the Mann-Whitney U Test were used to assess the level of significance because not all data were normally distributed and number of participants differed between the groups. Group membership was entered as an independent variable, and sociodemographic and clinical variables were entered as dependent variables. To improve clarity and ease of comprehension in tables and figures throughout the article, we decided to report generally the results of the parametric tests (ANOVA), except for those results of tests where nonparametric results differ from those for normally distributed data. This presentation aids the interpretation of the results. If dependent variables were categorical, we applied Fisher exact test. In addition, Cohen d was calculated for significant effects as descriptive measure of effect size (ES). Quantitative sensory testing data pre-processing and statistical analyses were performed according to the protocol established by Rolke et al.46 Most QST parameters (CDT, WDT, TSL, MPT, MPS, DMA, WUR, PPT, and mechanical detection threshold) are log-normally distributed and were therefore logtransformed.45 Analysis of variance was used to test for group differences. For post hoc tests, least significant difference test was used whenever appropriate.

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We also standardized all QST measures of subjects with nsCLBP using a z-transformation referring to the mean and SD of the control group. This procedure allowed for the direct comparison between sensory tests that are measured in different units (eg, ˚C and mN) as well as to judge whether there was a gain or loss of function in profiles between subjects with nsCLBP and controls. Z-values above “0” indicate hyperfunction, ie, patients are more sensitive to the tested parameter compared with controls (lower thresholds, gain of function), whereas z scores below “0” indicate hypofunction and therefore a loss of sensitivity of the patient compared with controls (higher thresholds). Whenever log-transformed scores were calculated, the log-scores were used for z-standardization and ANOVA. To avoid false positive results in multiple testing, the significance level for analysis of QST was set to P , 0.01. Sensitivity analyses were performed to determine the effect of outliers (number of subjects that ranked outside 6 1.96 SD).

3. Results A total of 180 subjects were recruited for this study, divided into nsCLBP-TE (n 5 56), nsCLBP-W-TE (n 5 93), and pain-free controls (n 5 31). Table 1 presents the sociodemographic characteristics of the participants. There were no significant differences in age, sex, body mass index, status of relationship, education level, and working status between groups. 3.1. Pain Although nsCLBP-TE and nsCLBP-W-TE differed significantly in back pain intensity, duration of back pain, functional back capacity, and quality of life to pain-free controls (P , 0.001), there were no significant differences in these variables between nsCLBP-TE and nsCLBP-W-TE. The nsCLBP-TE reported significantly higher numbers of painful areas compared with the nsCLBP-W-TE (7.0 6 2.3 vs 6.1 6 2.5, ES: 0.35, P , 0.001; Fig. 1); however, the overall proportion of participants with widespread pain did not differ between the groups (69.6% against 66.7%, P 5 0.857); nsCLBP-TE reported pain in the head area significantly more often than nsCLBP-W-TE (66.7% against 43.0%, P 5 0.006), whereas there were no significant differences between groups for the other body regions. Regarding the quality of pain referred to the specific physical sensations associated with the pain, nsCLBP-TE revealed significantly higher sensory pain experiences compared with nsCLBP-W-TE (19.6 6 7.1 vs 17.0 6 6.5, ES: 0.38, P , 0.001), whereas the differences in the affective pain experience did not reach the level of significance. Taking pain relief medication was more frequently observed in nsCLBP-TE compared with nsCLBPW-TE (56.4% vs 37.6%, ES: 0.36, P 5 0.040). For further details, see Table 1. 3.2. Psychological assessment In the nsCLBP-TE, traumatic events (according to criterion A) were described as serious accidents (n 5 7, 12.5%), witness of traumatic event (n 5 7, 12.5%), violent assaults (n 5 12, 21.4%), natural disasters (n 5 2, 3.6%), sexual assaults (n 5 1, 1.8%), sexual contact when less than 14 years of age by someone .5 years older (n 5 9, 16.1%), or as “other types of traumatic exposure” (n 5 18, 32.1%). The severity of trauma-associated symptoms as indicated by the PDS-D sum score was 9.2 6 9.9. None of the subjects met the full diagnostic criteria for PTSD. In the control group, 7 of 31 subjects reported exposure to traumatic events in the past. Compared with pain-free controls, the scores for symptoms of anxiety as assessed by HADS indicated significantly higher

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Figure 1. Number of painful areas: percentage of subjects who reported pain in the indicated area. The locations where pain was felt were indicated on the outline of the body: (A) participants with nonspecific chronic low back pain (nsCLBP) and trauma exposure (TE) (nsCLBP-TE); (B) participants with nsCLBP without TE (nsCLBP-W-TE). Participants with nsCLBP and TE reported pain in the head area significantly more often (P 5 0.006) than nsCLBP-W-TE, whereas there were no significant differences between groups for other body areas. L, left; R, right.

anxiety values in participants with nsCLBP (nsCLBP-TE: ES: 1.45, P , 0.001; nsCLBP-W-TE: ES: 0.76, P , 0.001), and nsCLBP-TE reported significantly higher anxiety scores compared with nsCLBP-W-TE (ES: 0.45, P 5 0.006). Separating patients those with conspicuous and inconspicuous anxiety levels, there was no significant group difference (36% of nsCLBPTE and 30% of nsCLBP-W-TE, P 5 0.470). Hospital Anxiety and Depression Scale means for symptoms of depression indicated significantly higher scores in participants with nsCLBP compared with controls (nsCLBP-TE: ES: 1.08, P , 0.001; nsCLBP-W-TE: ES: 0.71, P 5 0.001), but no differences between nsCLBP-TE and nsCLBP-W-TE. 3.3. Quantitative sensory testing

3.3.2. Comparison of QST values of the hand dorsum Similar to the somatosensory profiles of the back, ANOVA of QST values of the hand dorsum revealed significant group differences only for PPT (0.006; Table 3). Compared with nsCLBP-W-TE and pain-free controls, nsCLBP-TE showed a reduced PPT (ES: 0.40 and ES: 0.69, respectively; P 5 0.01 and P 5 0.003, respectively), whereas there were no significant differences between nsCLBPW-TE and pain-free controls. There were no significant group differences within the stimulus–response functions of pinprick pain on the hand. No signs of punctate mechanical hyperalgesia or PHS were found for nsCLBP-TE, nsCLBP-W-TE, or the control group. As with the PPT of the back, hand PPT was significantly correlated with trauma symptom severity, anxiety, and depression (r 5 20.222, r 5 20.239, r 5 20.269, P , 0.001, respectively).

3.3.1. Comparison of QST values of the back As shown in Table 2, ANOVA revealed significant group differences only for PPT (P 5 0.001). Compared with pain-free controls, back pain subjects showed reduced PPTs (nsCLBP-TE: ES: 0.87, P , 0.001; nsCLBP-W-TE: ES: 0.46, P 5 0.004), whereas nsCLBP-TE had significantly lower PPTs compared with nsCLBP-W-TE (ES: 0.41, P 5 0.019). There were no significant group differences within the stimulus–response functions of pinprick pain on the back. No signs of punctate mechanical hyperalgesia or PHS were found for nsCLBP-TE, nsCLBP-W-TE, or the control group. Exploratory correlation analyses of the back PPT with trauma symptom severity, anxiety, and depression revealed significant correlations (r 5 20.205, r 5 20.274, r 5 2 0.205, P , 0.001, respectively).

3.3.3. Localized vs generalized sensory changes In nsCLBP-W-TE, the PPT of the back was significantly reduced compared with the PPT of the hand. In contrast, nsCLBP-TE showed similar alterations of the PPT for both areas (Fig. 2). Thus, alterations in nsCLBP-W-TE were localized in the painful area in the back and alterations in nsCLBP-TE were generalized in space (painful area in the back and pain-free dorsum of the hand). 3.3.4. Sensitivity analyses and assessment for outliers In total, 17 of all PPT parameters (4.7%) were outside the 95% confidence interval (CI) of their respective group, which is close to the expected value of 5%. Sensitivity analyses by excluding outliers confirmed the stability of effects. This indicates that the results were

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Table 2

Somatosensory profiles of the back obtained by QST.

CDT, D˚C WDT, D˚C TSL, ˚C CPT, ˚C HPT, ˚C PPT, kg/cm2 MPT, mN MPS, NRS0/100 DMA WUR MDT, mN VDT/8

nsCLBP-TE

nsCLBP-W-TE

Controls pain-free

Mean (95% CI)

Mean (95% CI)

Mean (95% CI)

0.23 (0.15; 0.31) 0.38 (0.32; 0.43) 0.65 (0.59; 0.71) 17.62 (14.6; 20.7) 42.11 (41.1; 43.1) 0.60 (0.54; 0.67)C,W 1.28 (1.15; 1.40) 0.47 (0.30; 0.64) 20.93 (21.00; 20.86) 0.40 (0.34; 0.47) 0.69 (0.54; 0.84) 2.85 (1.98; 3.71)

0.25 (0.19; 0.31) 0.41 (0.37; 0.45) 0.67 (0.62; 0.72) 18.38 (16.2; 20.6) 42.07 (41.3; 42.9) 0.69 (0.65; 0.73)C,T 1.33 (1.24; 1.43) 0.32 (0.20; 0.43) 20.96 (20.98; 20.93) 0.46 (0.40; 0.51) 0.76 (0.67; 0.86) 4.34 (3.68; 4.99)

0.23 (0.13; 0.34) 0.39 (0.33; 0.44) 0.64 (0.57; 0.72) 14.62 (10.5; 18.7) 42.98 (41.6; 44.3) 0.77 (0.72; 0.83)T,W 1.30 (1.13; 1.48) 0.39 (0.15; 0.63) 20.97 (21.00; 20.94) 0.29 (0.20; 0.38) 0.77 (0.60; 0.93) 4.35 (3.19; 5.51)

F

P

0.123 0.549 0.222 1.332 0.706 6.992 0.261 1.123 0.713 4.684 0.393 4.269

0.884 0.579 0.801 0.267 0.495 0.001 0.770 0.328 0.492 0.010 0.676 0.017

P value calculated by 1-way ANOVA for between-group comparisons; LSD for post hoc tests (C, significantly different compared with controls; T, significantly different compared with participants with nsCLBP-TE; W, significantly different compared with participants with nsCLBP-W-TE). F, test statistic. Values for CDT, WDT, TSL, PPT, MPT, MPS, DMA, WUR, and MDT are logarithmically transformed because they are normally distributed in log-space. QST, quantitative sensory testing; nsCLBP, nonspecific chronic low back pain; nsCLBP-TE, participants with nsCLBP and TE; nsCLBP-W-TE, participants with nsCLBP without TE; CI, confidence interval; CDT, cold detection threshold; WDT, warm detection threshold; TSL, thermal sensory limen; CPT, cold pain threshold; HPT, heat pain threshold; PPT, pressure pain threshold; MPT, mechanical pain threshold; MPS, mechanical pain sensitivity; NRS0/100, numerical rating scale; DMA, dynamic mechanical allodynia; WUR, wind-up ratio; MDT, mechanical detection threshold; VDT, vibration detection threshold; ANOVA, analysis of variance; LSD, least significant difference.

not based on pathological outliers within the respective groups. Compared with the control group, several individual values were outside the 95% CI of the control group (and considered abnormal): 25% in the nsCLBP-TE group and 17% in the nsCLBP-W-TE group ranged outside the 95% CI of the control group; thus patients with TE had more pathological sensory test results. Additional sensitivity analyses comparing controls with TE to those controls without TE revealed no differences in PPT at the hand (means 0.66 kg/cm2 vs 0.65 kg/cm2, respectively) between those 2 groups and only small differences for PPT at the back (means 0.81 kg/cm2 vs 0.76 kg/cm2), with higher PPT in the controls with TE. This finding underpins our results because we found lower PPT in the nsCLBP-TE. In general, rerunning analyses using nonparametric tests produced similar results. None of the comparisons that were not significant with parametric tests became significant when nonparametric tests were used. In addition, none of the significant comparisons lost its significance, when nonparametric tests were applied.

4. Discussion The aim of this study was to determine whether TE is accompanied by specific alterations in pain perception in subjects with nsCLBP. For this purpose, we used a comprehensive clinical evaluation including structured clinical interview (SCID) and a standardized QST protocol to assess the somatosensory profiles of nsCLBP-TE and to compare them with nsCLBP-W-TE. In addition, pain-free controls were measured. The most important findings were that compared with controls, nsCLBP-TE presented lower pain thresholds in both the pain-free area (hand) and the pain-affected area (back). In contrast, nsCLBP-W-TE presented lower pain thresholds only in the painaffected area, but not in the pain-free area. These differences in somatosensory function were seen for PPTs only as a measure of hyperalgesia from deep somatic tissues (ie, muscle and fascia). This suggests hyperalgesia to deep pain modalities generalized in space in nsCLBP-TE, whereas nsCLBP-W-TE show only localized alterations with decreased thresholds only in the pain-affected area of the back. In addition, nsCLBP-TE exhibited more pathological

Table 3

Somatosensory profiles of the hand obtained by QST.

CDT, D˚C WDT, D˚C TSL, ˚C CPT, ˚C HPT, ˚C PPT, kg/cm2 MPT, mN MPS, NRS0/100 DMA WUR MDT, mN VDT/8

nsCLBP-TE

nsCLBP-W-TE

Controls pain-free

Mean (95% CI)

Mean (95% CI)

Mean (95% CI)

0.10 (0.04; 0.16) 0.42 (0.35; 0.49) 0.58 (0.50; 0.66) 15.80 (13.03; 18.58) 43.78 (42.75; 44.82) 0.54 (0.49; 0.59)C, W 1.65 (1.53; 1.77) 0.31 (0.15; 0.47) 20.97 (20.99; 20.95) 0.34 (0.27; 0.41) 0.48 (0.36; 0.60) 7.25 (7.05; 7.45)

0.14 (0.07; 0.20) 0.51 (0.44; 0.58) 0.66 (0.60; 0.73) 15.85 (13.69; 18.02) 44.93 (44.14; 45.71) 0.61 (0.58; 0.64)T 1.71 (1.62; 1.81) 0.13 (0.03; 0.24) 20.97 (21.00; 20.94) 0.39 (0.33; 0.45) 0.45 (0.38; 0.53) 7.30 (7.17; 7.44)

0.15 (0.05; 0.25) 0.51 (0.39; 0.63) 0.66 (0.55; 0.77) 10.42 (7.17; 13.66) 45.27 (43.92; 46.63) 0.65 (0.60; 0.69)T 1.70 (1.51; 1.89) 0.24 (0.05; 0.43) 20.97 (21.00; 20.94) 0.31 (0.22; 0.41) 0.35 (0.19; 0.51) 7.26 (7.03; 7.50)

F

P

0.482 1.607 1.383 3.636 2.107 5.325 0.340 2.054 0.017 1.146 1.002 0.121

0.619 0.203 0.254 0.028 0.125 0.006 0.712 0.131 0.983 0.320 0.369 0.886

P value calculated by 1-way ANOVA for between-group comparisons; LSD for post hoc tests (C, significantly different compared with controls; T, significantly different compared with participants with nsCLBP-TE; W, significantly different compared with participants with nsCLBP-W-TE). F, test statistic. Values for CDT, WDT, TSL, PPT, MPT, MPS, DMA, WUR, and MDT are logarithmically transformed because they are normally distributed in log-space. QST, quantitative sensory testing; nsCLBP, nonspecific chronic low back pain; nsCLBP-TE, participants with nsCLBP and TE; nsCLBP-W-TE, participants with nsCLBP without TE; CI, confidence interval; CDT, cold detection threshold; WDT, warm detection threshold; TSL, thermal sensory limen; CPT, cold pain threshold; HPT, heat pain threshold; PPT, pressure pain threshold; MPT, mechanical pain threshold; MPS, mechanical pain sensitivity; NRS0/100, numerical rating scale; DMA, dynamic mechanical allodynia; WUR, wind-up ratio; MDT, mechanical detection threshold; VDT, vibration detection threshold; ANOVA, analysis of variance; LSD, least significant difference.

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Figure 2. Quantitative sensory testing (QST) profiles: somatosensory profiles at the hand dorsum (A) and lumbar back area (B). Test areas were distributed on the thenar eminence and the back of the ipsilateral hand and on the autochthonous back muscles at the height of lumbar segments L1 to L5 of the low back area (5 6 0.5 cm next to the midline). Values are mean 6 SEM. Z values: nsCLBP values were standardized according to the mean and SD of pain-free controls. **P , 0.01 for difference between participants with nsCLBP and trauma exposure (TE) (nsCLBP-TE) and participants with nsCLBP without TE (nsCLBP-W-TE). (C), significantly different to controls. CDT, cold detection threshold; WDT, warm detection threshold; TSL, thermal sensory limen; CPT, cold pain threshold; HPT, heat pain threshold; PPT, pressure pain threshold; MPT, mechanical pain threshold; MPS, mechanical pain sensitivity; DMA, dynamic mechanical allodynia; WUR, wind-up ratio; MDT, mechanical detection threshold; VDT, vibration detection threshold.

QST values, and hyperalgesia to PPT at the back was more pronounced than in CLBP-W-TE. Thus, we can conclude that there are distinct sensory profiles in nsCLBP-TE and nsCLBP-W-TE. Our finding of decreased thresholds for deep pain at the affected back area is consistent with other research, which found mechanical hyperalgesia to deep stimuli in CLBP subjects.5,7,21,51 In the previous literature, this somatosensory profile could at least partially be attributed to peripheral sensitization in these subjects possibly due to localized alterations in the myofascial tissue and joints. However, recent animal studies demonstrated that central processes at the spinal level are also involved.27 In contrast to nsCLBP-W-TE, nsCLBP-TE demonstrated hyperalgesia to deep stimuli generalized in space. Such enhanced pain sensitivity to deep stimuli even outside the areas of clinical pain suggests abnormalities in central pain processing rather than damage or inflammation of peripheral structures.21 It is possible that multiple neuronal mechanisms such as descending disinhibition, central sensitization, and lack of habituation may work together. Noteworthy, compared with controls, WUR did not reveal group differences at the hand and only marginal differences at the back for nsCLBP-W-TE, but not for nsCLBP-TE. While wind-up comprises a NMDA receptor–dependent summation at spinal wide dynamic range neurons, this phenomenon is independent of longlasting central sensitization at spinal synapses.38,54 Thus, our findings indicate that an involvement of central processes other than those WUR-associated processes at spinal neurons might be of primary relevance in nsCLBP-TE.

In addition, nsCLBP-TE was also more severely burdened by clinical and psychological factors. They reported higher sensory pain experience, higher number of painful areas, higher intake of pain medication, and higher anxiety than nsCLBP-W-TE. The higher levels of anxiety could have accounted at least partially for the differences in PPT between nsCLBP-TE and nsCLBP-W-TE, as research suggests that anxiety is associated with clinical pain intensity.6,8,12 This is also suggested by explorative statistical analysis in our study (data not shown). However, group means for anxiety were in the lower range, and group differences are probably not clinically relevant as supported by equal proportion of participants with inconspicuous/conspicuous levels within both groups. However, future research should pay more attention to the role of anxiety in pain patients with TE. The results of this study are consistent with those observed in earlier studies addressing pain-free subjects with TE. Creech et al.10 found that lifetime history of trauma was associated with lower ischemic pain tolerance in female students. Similarly, ´ınez23 demonstrated higher pain Gomez-P ´ erez ´ and Lopez-Mart ´ ratings in the cold pressor task in trauma-exposed female students compared with non-trauma–exposed controls. In that study, trauma-exposed women with and without PTSD reported higher pain unpleasantness than non-trauma–exposed controls, suggesting that the TE itself, and not the development of PTSD symptoms after the event, may explain these differences. However, as both studies were limited to pain-free subjects, those data do not allow us to reach any conclusions about the

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role of TE in nsCLBP subjects. Our findings indicate for the first time that augmented central pain processing may be involved in subjects with nsCLBP who had experienced TE and suggest that biological mechanisms distinct from those related to tissue injury may contribute to pain augmentation after TE. Notably, although the alterations in sensory profiles observed in our study in nsCLBP-TE were generalized in space (pain-affected area in the back and non-painful area at the hand), they did not involve all nociceptive submodalities. Significant differences in pain thresholds compared with controls were only seen for PPT. Pressure pain primarily reflects myofascial nociception,31 whereas thresholds for thermal and pinprick stimuli reflecting skin nociception29 remained unaffected. This is in contrast to some other generalized pain syndromes related to abnormal central pain processing, eg, fibromyalgia, in which increased sensitivity is both generalized in space (back/hand) and across different nociceptive submodalities (superficial/deep pain).5 In fibromyalgia, the dysfunctional descending inhibitory control of pain is believed to be closely involved in its pathogenesis. In contrast, deep pain hyperalgesia as observed in our study has been related particularly to central pain amplification processes.21 This is also supported by recent functional imaging studies that have demonstrated augmented central pain processing in nsCLBP.21 However, more work is required to investigate the underlying central mechanisms in more detail. It is interesting to note that nsCLBP-TE revealed higher pain sensitivity in the back compared with nsCLBP-W-TE. This suggests that TE may act as an “additional” amplification factor for nsCLBP. In line with that, among all nsCLBP participants, those with TE were significantly more likely to have used any medication for pain control compared with those without TE. Posttraumatic stress disorder is known to be associated with an increased medication use in clinical and community samples44; however, for nsCLBP patients, the relationship with TE but without PTSD has not been described so far, and further work is required to establish this relationship. It is somewhat surprising that although there were objective differences in deep pain sensitivity of the back area between nsCLBP-TE and nsCLBP-W-TE, there were no differences with respect to back pain intensity, the duration of back pain, the functional back capacity, or the quality of life between those 2 groups. That means that although there are objective differences in the psychophysiological somatosensory patterns, the clinical manifestations are to a large extent very similar. This corresponds well to the clinical experience in dealing with nsCLBP, in which the identification of the underlying neurophysiological mechanisms remains a major challenge. Against this background, it is worth mentioning that nsCLBP-TE and nsCLBP-W-TE additionally differed in the number of painful areas. This finding seems to be consistent with epidemiological research, which highlighted the association of widespread pain with TE.1,2,25 Moreover, these findings correspond well with our psychophysiological findings of sensory alterations generalized in space and also with the idea of an augmented central pain processing in nsCLBP-TE. However, this hypothesis has never been directly targeted, so further work will be required to establish this mechanism. The findings of this study have some implications for future practice. If the symptoms in a substantial number of subjects with nsCLBP are due to abnormal central pain processing rather than damage or inflammation of peripheral structures, this would suggest that these subjects should be approached from a more “central” point of view rather than be fixed to the back area. Based on our results, specific consideration should be given in particular to the careful evaluation of nsCLBP patients for previous TE. In cases in which evidence for psychological trauma exists,

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therapists should actively screen for further signs of generalized pain augmentation (eg, low PPT at neutral sites, additional painful areas). Such procedures offer the possibility of introducing early on a more specific therapeutic strategy for the affected patients. Several limitations of this study must be taken into account. First, all analyses were based on cross-sectional data, thus it is not possible to infer causation or directionality between TE and the alterations in pain perception shown in our study. Furthermore, our controls included participants with and without TE. Although it would have been desirable to separate control participants with and without TE, this was not possible because of the small number of participants with TE in the control group. However, descriptive analysis of PPT demonstrated that both groups show equal values at the hand, but control participants with TE show slightly higher values at the back. This even underpins our findings because we found lower PPT also in nsCLBP-TE compared with nsCLBP-W-TE. Furthermore, composition of the control group does not impair the comparison between nsCLBP-TE and nsCLBP-W-TE. Taken together, our data indicate for the first time that there are distinct sensory profiles in nsCLBP-TE and nsCLBP-W-TE (but without PTSD diagnoses). Our findings suggest an augmented central pain processing in nsCLBP-TE and a localized decrease in deep pain thresholds in nsCLBP-W-TE, suggesting to regional sensitization. In addition, trauma symptom severity seems to correlate with the magnitude of hyperalgesia. This finding may explain why traumatic events are associated with an increased prevalence of chronic pain conditions.

Conflict of interest statement The authors have no conflicts of interest to declare.

Acknowledgements The authors wish to thank Beate Eisenecker for her excellent technical assistance. Involved co-workers were supported by the German Federal Ministry of Education and Research (Bundesministerium fur ¨ Bildung und Forschung; LOGIN consortium, FKZ: 01EC1010A and 01EC1010B). The submitted article does not contain information about medical device(s)/drug(s). No benefits in any form have been or will be received from a commercial party directly or indirectly related to the subject of this article. Article history: Received 28 July 2014 Received in revised form 24 November 2014 Accepted 16 December 2014 Available online 9 January 2015

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