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Recurrent low back pain patients demonstrate facilitated pronociceptive mechanisms when in pain, and impaired antinociceptive mechanisms with and without pain

McPhee, Megan E.; Graven-Nielsen, Thomas*

doi: 10.1097/j.pain.0000000000001679
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Low back pain (LBP) has been inconsistently associated with enhanced pronociceptive and impaired antinociceptive mechanisms. It remains unknown whether alterations are causal, consequential, or coincidental to pain presence. This study investigated pronociceptive and antinociceptive mechanisms in recurrent LBP (RLBP) patients across painful and pain-free periods, compared with age/sex-matched asymptomatic controls. During a painful episode (day 0) and when pain-free (day 28), 30 RLBP patients were assessed and compared with 30 controls over the same timeframe. Pressure pain thresholds were recorded bilaterally on the arm, back, and leg. Cuff algometry was used to assess cuff pressure pain detection threshold and cuff pain tolerance threshold on the lower legs, as well as temporal summation of pain (10 repeated painful cuff test stimuli on the dominant leg scored on a visual analogue scale) and conditioned pain modulation ([CPM]: cuff pain detection/tolerance threshold on dominant leg, before vs during painful cuff conditioning on the contralateral leg). Recurrent LBP patients displayed reduced pressure pain thresholds at the arm and back on day 0 compared with day 28 (P < 0.047) and with controls on day 0 (P < 0.049). Cuff pain detection threshold was reduced, and ratings of suprathreshold test stimuli were increased in RLBP patients on day 0 compared with day 28 (P < 0.02). Temporal summation of pain magnitude (increase in visual analogue scale scores) was enhanced in RLBP participants on day 0 compared with day 28 (P = 0.027) and with controls on day 0 (P = 0.039). Conditioned pain modulation magnitude (increased threshold during conditioning) was lower overall in RLBP participants than in controls (P = 0.021). Enhanced pronociceptive mechanisms were observed in RLBP patients. When pain-free, measures returned to similar levels as controls, except for CPM, which remained impaired.

Widespread pressure hyperalgesia and facilitated pronociception in low back pain patients were only present during a painful episode, whereas antinociception remained impaired in pain-free periods.

Center for Neuroplasticity and Pain (CNAP), SMI, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark

*Corresponding author. Address: Department of Health Science and Technology, Faculty of Medicine, Center for Neuroplasticity and Pain (CNAP), SMI, Aalborg University, Fredrik Bajers Vej 7 D3, Aalborg DK-9220, Denmark. Tel.: +45 9940 9832; fax: +45 9815 4008. E-mail address: tgn@hst.aau.dk (T. Graven-Nielsen).

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

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

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1. Introduction

In painful conditions, the assessment of pain mechanisms has received increasing attention as a way to probe the role of pain-related neuroplasticity.4 As such, many cross-sectional studies have examined differences between pain patients and pain-free individuals, generally showing patients to have pain mechanisms with a more pronociceptive profile.4,28,32,45 However, in low back pain (LBP) specifically, findings are highly variable.28 From such cross-sectional studies, there are common reports of local and/or widespread hyperalgesia9,11,20,48 and other enhanced pronociceptive mechanisms (eg, temporal summation of pain [TSP]),8,9,17,61 but conflicting results for antinociceptive mechanisms (eg, conditioned pain modulation [CPM]).11,31,39,60

One possibility is that observed alterations in pronociceptive and antinociceptive measures are consequential to the presence of ongoing pain and disability, and thus fluctuate with the pain experience, potentially explaining conflicting results. In line, there are varying degrees of evidence to suggest that provoking nociceptive activity and thus experimental pain can impair or facilitate these phenomena (Hoeger Bement, et al. unpublished data),5 and successfully treating clinical pain by removing effects of peripheral sensitization21,25 can enhance or restore pronociceptive and antinociceptive measures. The alternative explanation is that differences in pain mechanisms precede the onset of a pain condition and thus could be used to predict persistent pain development. Consistent with this, there is preliminary evidence to suggest that early changes in pain sensitivity may be associated with persistence of spinal pain,37,51, and that preoperative47,64 or preinjury7,38 pain sensitivity testing can partly explain variability in postoperative or postinjury pain severity. However, despite these existing indications on the nature of the relationship between pain sensitivity and pain development, confounding factors (ie, pain presence during assessments, extrinsic provocation of pain, or lack of control comparators) make it difficult to draw firm conclusions on the possibility of preexisting sensitisation.

For LBP, pain sensitivity measures of most relevance are those assessing deeper musculoskeletal structures implicated in the clinical pain, with pressure modalities suggested to have high discriminative ability.42 Handheld and cuff pressure algometry are reliable tools used to assess sensitivity to superficial and deep pressure, respectively.6,24,62 Furthermore, cuff algometry has been shown to be a reliable user-independent method of assessing nociceptive facilitation and inhibition from deep tissues,10,23,24,29 through TSP and CPM paradigms, respectively.

To explore whether alterations in pain sensitivity may be a consequence of pain presence, this study intended to assess a group of participants with subclinical recurrent LBP (RLBP) during a painful episode and when pain-free again 1 month later. Furthermore, to assess the magnitude of alteration in pain sensitivity, participants were compared with age- and sex-matched pain-free individuals. It was hypothesised that participants with RLBP would show hyperalgesia, enhanced TSP, and reduced CPM during the painful period compared to the pain-free participants, with maintenance of these alterations during the pain-free period expected.

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2. Methods

2.1. Participants

Participants with recurrent LBP and healthy age- and sex-matched controls, fluent in English, were recruited from the university setting and wider community, through social media and advertisements in recreational facilities, fitness centres, clinics, and on local notice boards. All participants underwent a verbal information meeting before inclusion, and those with current acute lower limb pain, chronic pain, neurological, musculoskeletal, cardiorespiratory, or mental disorders were excluded. In addition, participants with RLBP underwent a thorough patient history to ensure that they met the recommended criteria55 with pain between the lower costal margin and gluteal folds for more than 24 hours at the time of recruitment and with more than one LBP episode in the preceding 12 months. Due to the premise of the study, RLBP participants also needed to have current LBP during the first experimental session and be expected to recover to pain-free within 4 weeks, based on individual experience with previous LBP episodes. Healthy pain-free participants must not have had a history of significant LBP (ie, LBP lasting more than 24 hours, not due to unaccustomed exercise), could not be experiencing pain of any origin during either experimental session, and had to match an RLBP participant in both age (±1 year) and sex.

Using G*Power 3.1.9.2 (Kiel University, Germany), a priori sample size calculations were performed based on previous cuff algometry reliability data. For the main analysis of variance (ANOVA) with 2 groups and 2 time points at an alpha level of 0.05 and 80% power, a minimum of 22 participants per group would be required to show significant within-between interactions of moderate effect size (f > 0.25). Due to the risk of dropouts and nonresolution of pain over the study timeframe, the aim was to recruit and include 30 participants per group.

Before participation, all participants were provided written and verbal information, and all participants provided written informed consent. The protocol was approved by the local ethical committee (Den Videnskabsetiske Komité for Region Nordjylland, N-20170034), was preregistered on ClinicalTrials.gov (NCT03463759), and was conducted in accordance with the Declaration of Helsinki.

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2.2. Experimental protocol

Two 2-hour sessions were conducted with each participant, at the same time of day, with an approximate 4-week interval (Fig. 1). If the LBP episode had not resolved by 4 weeks, the second session was rescheduled for 1 week later, to a maximum interval of 6 weeks (pain-free participants' intersession intervals were matched where possible). At the beginning of each session, demographic information was recorded, and participants completed a series of questionnaires on pain history, sleep, mood, menstruation, physical activity, and pain-related distress. Participants with RLBP completed additional questionnaires to characterise their LBP intensity, quality, and distribution, pain-related disability, and presence of neuropathic features. A short clinical examination was then conducted, including a brief patient history for those with RLBP, and physical examination to ensure painful/pain-free spinal movement as appropriate to group assignment. In each session, pressure pain thresholds (PPTs) were then recorded three times bilaterally over the extensor carpi radialis (ECR), upper trapezius (UT), first (L1) and fifth (L5) segments of lumbar erector spinae, and gastrocnemius (GAS) muscles. Finally, cuff algometry was used over the lower legs to record cuff pressure pain detection threshold (PDT) and pain tolerance threshold (PTT), and assess both TSP and CPM.

Figure 1.

Figure 1.

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2.3. Demographics, history, and questionnaires

Demographic information collected included age, sex, body mass index, and hand and leg dominance. Participants then estimated their sleep duration for the preceding night, and female participants answered questions regarding menstrual regularity and current day of cycle. All participants then completed the International Physical Activity Questionnaire, which estimates weekly energy expenditure based on self-reported daily hours of activity26; the Pain Catastrophizing Scale (PCS), which characterises distressing thoughts related to painful experiences58; and rated their current mood on the Faces Scale (1-20, 1 = most positive).33

In the first session, participants with RLBP answered questions about their usual frequency and duration of painful episodes and pain-free periods, the number of years since their first ever LBP episode, and clinical features of the pain. Low back pain intensity and unpleasantness was then rated on visual analogue scales (VAS; 0 = no pain/unpleasantness, 10 = worst pain/most unpleasantness sensation imaginable), for current pain (sitting) and maximum pain (since pain onset). Pain area was then drawn on an electronic body chart (Navigate Pain, Aalborg University) for 2 different conditions: first, when the participant imagined sitting comfortably, then when imagining bending/moving/lifting; and the size of pain areas (in pixels) were extracted. Additional questionnaires were also completed including: the Roland-Morris Disability Questionnaire, which scores daily function impacted by the back pain (maximum score = 24, highest disability)49; and the Pain-DETECT Questionnaire, which characterises the presence of neuropathic pain-like symptoms.15 Participants were also asked to keep a pain diary (morning and evening VAS LBP intensity rating) for the 4 weeks of the study period, and estimate total episode length at the second session.

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2.4. Physical examination

Lumbar flexion and extension range-of-motion were measured as the change in distance between the T12 and sacrum, from upright stance to end of range, using a manually anchored tape measure. The presence of pain on movement and the most aggravating movement direction was recorded. A passive straight leg raise was performed on each leg to first onset of stretch/pain, with dorsiflexion added as a provocative manoeuvre, and provocation of usual back pain recorded as a positive test.

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2.5. Pressure pain thresholds

Pressure pain thresholds (PPTs) were assessed using a rubber-tipped handheld pressure algometer (Somedic, Norra Mellby, Sweden) with 1-cm2 contact area. Pressure was increased at a rate of 30 kPa/second until the participant indicated that the pressure became painful by pressing a button, at which point the pressure was recorded. Pressure pain thresholds were assessed bilaterally over the: ECR (3 cm distal to the lateral epicondyle along a line toward the radial condyle), UT (midway between the C7 spinous process and the acromion), L1 and L5 (3.5 cm lateral to the L1 and L5 spinous processes, over the erector spinae muscle/fascial bulk), and GAS (midway between the popliteal line and calcaneal tuberosity) muscles. Assessments were randomized to start on the right or left side first, 3 repetitions were performed at each site and averaged across repetitions and sides for analysis, with >2 minutes' interval between reassessment of the same site.

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2.6. Cuff pressure pain sensitivity

Cuff pressure pain sensitivity was assessed using a computer-controlled cuff algometry system (Nocitech, Aalborg University, Denmark), paired with two 10-cm wide tourniquet cuffs (VBM Medizintechnik GmbH, Sulz am Neckar, Germany) and an electronic-VAS (eVAS). The eVAS was anchored with “no pain” as 0 cm and “worst pain imaginable” as 10 cm. The cuffs were placed over the widest portion of each lower leg, approximately 5 cm below the tibial tuberosity. Pressure was increased slowly at a rate of 1 kPa/second to a maximum of 100 kPa (device safety limit) on each leg, and participants were instructed to begin moving the eVAS dial upward when the pressure became painful, to keep rating as the pressure pain increased, then to press the “stop” button when they could no longer tolerate further increases in pressure pain. Cuff PDT (cPDT) was defined as the pressure when the eVAS passed 1 cm, cuff PTT (cPTT) was defined as the pressure immediately before pressing the stop button, and the eVAS rating immediately before pressing the stop button was extracted (eVAS at cPTT). Cuff PDT, cPTT, and eVAS at PTT were assessed on each leg before other cuff assessments and averaged across sides for analysis.

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2.7. Suprathreshold cuff stimulation

Three single cuff pressure stimuli set at cPTT intensity recorded in the same session were performed on the dominant leg. Each time, the cuff was inflated at 100 kPa/second to reach cPTT pressure, remained at that pressure for 1 second, and then deflated as fast as possible, with a 10-second break between stimuli. For each stimulus, the participant was instructed to rate the intensity of pain on the eVAS, then return the dial to zero each time. The maximum eVAS score for each stimulus was extracted and averaged for analysis.

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2.8. Temporal summation of pain

A series of ten 1-second cPTT stimuli were applied, with 1 second in-between (0.5 Hz). Participants were instructed to rate the pain intensity of the first stimulus quickly on the eVAS, then adjust as necessary for subsequent stimuli, if the pain was increasing or decreasing, without returning to zero. eVAS ratings were extracted for each stimulus. Normalized epochs were created by subtracting the first-stimulus eVAS rating and then averaging eVAS ratings of the second to fourth stimuli (I), fifth to seventh stimuli (II), and eighth to tenth stimuli (III) for analysis.

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2.9. Conditioned pain modulation

Conditioned pain modulation was assessed using cuff algometry, with ramped test stimuli (as above to assess cPDT and cPTT) applied to the dominant leg, and a conditioning stimulus of tonic cuff pressure applied to the nondominant leg. Four test stimuli were applied with 30-second rest in-between, with a fifth test stimulus applied approximately 5 minutes after conditioning. Simultaneous with the third stimulus, tonic cuff pressure at 70% cPTT (as assessed immediately prior) was applied and maintained until the end of the third stimulus. Initial pain intensity of the tonic conditioning stimulus was assessed using a verbal numerical rating scale (0 = no pain, 10 = worst pain imaginable). Cuff PDT and cPTT values were extracted for each test stimulus. The change in cPDT and cPTT from the first ramp to the second, (second minus first, sequential unconditioned), third (third minus first, during conditioning), fourth (fourth minus first, immediately after conditioning), and fifth (fifth minus first, 5 minutes after conditioning) ramps were calculated for analysis (named CPM effect).

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2.10. Statistics

All data were analysed using SPSS (v24.0; IBM, Armonk, NY). Data are reported as mean (±SD) or median (interquartile range) in text and tables, and as mean (SEM) in figures. Normality was assessed within groups using the Shapiro-Wilks test, and parametric or nonparametric analysis was used as appropriate. Differences in questionnaire responses, clinical features, and methodological factors were compared using independent-samples t-tests or Mann–Whitney U-tests (between-group: RLBP or control), paired t-tests, or Wilcoxon signed rank tests (between-session: day 0 or day 28), or two-way ANOVAs (Group: RLBP or control; and Session: day 0 or day 28) as appropriate.

For pain sensitivity outcomes (PPT, cPDT, cPTT, and eVAS at cPTT, eVAS scores to suprathreshold pressure stimuli, TSP, and CPM), a two-way mixed ANOVA (with additional repeated factors when multiple sites, thresholds, or stimuli were assessed within a session) was performed, with the between-subjects factor Group (RLBP or Control), and within-subjects factors Session (day 0 or day 28) and Site (ECR, UT, L1, L5, GAS; or dominant/nondominant), Stimulus (TSP: 3 normalised eVAS-epochs, CPM: one unconditioned and 3 conditioned stimuli normalized by subtraction to the first stimulus), and/or Threshold (cPDT or cPTT). For CPM, an additional analysis of nonnormalized data (ie, five raw cPDTs and cPTTs) was undertaken within groups, with planned contrasts conducted after these analyses between the first threshold and each subsequent threshold, to confirm the presence of inhibition (supplementary material, available at http://links.lww.com/PAIN/A862). Intraclass correlation coefficients (ICC(3, k)) were also performed on repeated tests (PPT, cPDT, cPTT, eVAS at cPTT, and eVAS scores to suprathreshold pressure stimuli) within session for each group, and repeated tests (PPT, cPDT, cPTT, eVAS at cPTT, eVAS scores to suprathreshold pressure stimuli, TSP, and CPM) between sessions for the control group, based on a two-way mixed model with consistency definition, and are included in the supplementary material (available at http://links.lww.com/PAIN/A862). Exploratory Pearson or Spearman correlational analysis was undertaken to identify potential explanatory relationships between demographic (age, sex, body mass index), questionnaire (mood, sleep, International Physical Activity Questionnaire, PCS, Roland-Morris Disability Questionnaire, Pain-DETECT), or clinical (flexion, extension, pain intensity, unpleasantness, area, RLBP duration, and current episode duration) data, and psychophysical testing (PPT, cPDT, cPTT, eVAS on suprathreshold stimuli, TSP, and CPM of cPDT and cPTT) within each session. Post hoc pairwise comparisons or planned contrasts were conducted as indicated with Bonferroni correction. Significance was accepted at P < 0.05.

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3. Results

3.1. Participant characteristics

A total of 182 participants were screened to include 30 RLBP patients (27.3 ± 5.4 years; 16 males) and 30 matched controls in the experiment, although 1 RLBP patient was excluded after the first session due to the development of an unrelated medical condition (Table 1; and Supplementary Fig. 1, available at http://links.lww.com/PAIN/A862). All RLBP patients reported pain in the lower back region during the first session. By the second session after 28 days, the majority of patients were completely pain-free (n = 22), with the remainder either reporting only discomfort (n = 3, both pain intensity and unpleasantness VAS < 1/10) or no expectation of further recovery within 2 weeks (n = 3). Because the aim of the study was to compare painful and pain-free states among RLBP patients and healthy controls, participants still reporting pain in the second session were excluded from further analysis (n = 26 included). None of the control participants reported pain during either session (n = 30 included). Mood scores were generally positive, and sleep durations were within recommendations,27 with no differences observed between sessions or groups. Pain catastrophizing was higher in RLBP patients on day 0 (when in pain) compared with day 28 (F1,54 = 9.288, P < 0.004, η2 = 0.147; post hoc: P < 0.001) but was not different between groups during either session (P > 0.28, η2 < 0.022). Participants generally had greater flexion (F1,54 = 11.377, P < 0.002, η2 = 0.174) and extension (F1,54 = 7.045, P < 0.011, η2 = 0.115) range in the second session, and RLBP participants had less flexion range than controls (F1,54 = 7.206, P < 0.010, η2 = 0.118). Leg dominance (used for cuff measurements) was similar between groups (RLBP: 24 right, 2 left; Controls: 23 right, 7 left).

Table 1

Table 1

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3.2. Recurrent low back pain features

Patients reported pain of mild intensity and moderate unpleasantness on day 0 (Table 2), primarily in the lower back and occasionally extending toward the thoracic region or lower limbs (Fig. 2). Pain areas (total pixels coloured) were notably larger when imagining moving than when sitting comfortably at rest on day 0 (t25 = −5.09, P < 0.001, d = 0.48, Table 2 and Fig. 2). For the majority of patients, their pain was unlikely (n = 17) or uncertain (n = 9) to be neuropathic in origin, on the basis of PainDETECT scores. In this sample, repeated pain episodes of roughly 2 weeks had been present for a number of years, notably since adolescence (<20 years) in over half of the sample. Patients commonly reported their pain to be aggravated by prolonged static positioning and lumbar flexion or extension, reported mild disability as a result, and nearly half of the patients had consulted a physiotherapist or chiropractor in the past for their pain.

Table 2

Table 2

Figure 2.

Figure 2.

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3.3. Pressure pain sensitivity

Three-way ANOVA revealed a significant Group × Session × Site interaction (F3.0,160.5 = 4.87, P < 0.003, η2 = 0.083, Fig. 3). On post hoc testing, PPTs were found to be higher on day 28 than on day 0 at the ECR (P = 0.047, η2 = 0.071), UT (P = 0.007, η2 = 0.128), L1 (P = 0.003, η2 = 0.149), and L5 (P < 0.001, η2 = 0.293) sites, although not significantly at the GAS (P = 0.054, η2 < 0.068) site, in RLBP patients, but no differences were found between sessions for controls (all P > 0.05, η2 < 0.067). Pressure pain thresholds were also higher in Controls than in RLBP patients at the ECR (P = 0.024, η2 = 0.091), UT (P = 0.049, η2 = 0.070), L1 (P = 0.014, η2 = 0.106), and L5 (P = 0.033, η2 = 0.082) sites on day 0, but no between-group differences were observed on day 28 (P > 0.25, η2 < 0.003).

Figure 3.

Figure 3.

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3.4. Cuff pain sensitivity

Three-way ANOVA revealed a Group × Session × Threshold interaction (F1,54 = 4.381, P < 0.041, η2 = 0.075, Table 3), revealing that cPDT was higher for the RLBP group on day 28 than on day 0 (P = 0.020, η2 = 0.096). No differences between sessions were observed for cPDT or cPTT for the control group (P > 0.35, η2 < 0.017), nor between groups in either session (P > 0.39, η2 < 0.015). Two-way ANOVA of eVAS at cPTT ratings revealed no main effects or interactions of sessions or groups (P > 0.42, η2 < 0.013).

Table 3

Table 3

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3.5. Suprathreshold pressure pain ratings

Two-way ANOVA of suprathreshold cuff pressure stimuli eVAS ratings revealed a Group × Session interaction (F1,54 = 4.828, P < 0.032, η2 = 0.082, Table 3), with eVAS ratings being higher on day 0 than on day 28 for RLBP patients (P = 0.001, η2 = 0.200), but no differences were observed between sessions for controls (P > 0.47, η2 < 0.011) nor between groups in either session (P > 0.19, η2 < 0.032).

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3.6. Temporal summation of pain

Three-way ANOVA of normalised VAS epochs revealed a main effect of Epoch (F1.2,66.2 = 90.29, P < 0.001, η2 = 0.626, Fig. 4) and a Group × Session interaction (F1,54 = 4.35, P = 0.042, η2 = 0.074). Post hoc testing showed that each epoch was higher than the previous (I < II < III, P < 0.001, η2 > 0.652), demonstrating facilitation was observed during repeated stimulation. In addition, this facilitation was greater on day 0 than on day 28 for RLBP patients (P = 0.027, η2 = 0.087) and greater than Controls on day 0 (P = 0.039, η2 = 0.077), but no differences were seen between sessions in Controls (P > 0.54, η2 < 0.008) or between groups on day 28 (P > 0.67, η2 < 0.004).

Figure 4.

Figure 4.

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3.7. Conditioned pain modulation

Four-way ANOVA of CPM effects (change from Ramp 1 to Ramps 2-5 in cPDT and cPTT, respectively) revealed a main effect of Group (F1,54 = 5.62, P = 0.021, η2 = 0.094, Fig. 5), with Controls demonstrating higher CPM effects overall than RLBP patients (P = 0.021, η2 = 0.094). In addition, a Stimulus × Threshold interaction (F2.4,133.6 = 14.17, P < 0.001, η2 = 0.208) showed that immediately after conditioning (fourth Ramp), there was higher modulation of cPDT than cPTT (P = 0.012, η2 = 0.110), whereas at 5 minutes after conditioning (fifth Ramp), there was higher modulation of cPTT than cPDT (P = 0.002, η2 = 0.241). Moreover, for cPDT, modulation was higher during conditioning (third Ramp, P = 0.039, d = 0.59) and immediately after conditioning (fourth Ramp, P = 0.002, d = 0.83), and lower at 5 minutes after conditioning (fifth Ramp, P = 0.011, d = 0.60), than on the second ramp, meaning that there was generally immediate inhibition of cPDT due to conditioning. However, for cPTT, CPM magnitude was higher during conditioning (third Ramp, P < 0.001, d = 1.46), immediately after conditioning (fourth Ramp, P = 0.002, d = 0.75), and at 5 minutes after conditioning (fifth Ramp, P = 0.001, d = 0.90) than on the second ramp, suggesting significant and prolonged inhibition of cPTT overall. No differences were seen between sessions (P > 0.60, η2 < 0.006).

Figure 5.

Figure 5.

Conditioning pressure during CPM was higher on day 28 (36.2 ± 13.7 kPa) than on day 0 (34.1 ± 12.5 kPa; F1,54 = 4.96, P = 0.030, η2 = 0.084), but not significantly different between groups (P > 0.49, η2 < 0.010). The numerical rating scale scores of conditioning pain were not different between groups or sessions (4.3 ± 1.6 cm, F1,54 < 1.34, P > 0.25, η2 < 0.024).

All data were normally distributed for the control group, but 4 outliers (>2 SD from mean across measures) were noted in the RLBP group for some of the cPDT CPM effects. Removing them from the analysis increased the magnitude of overall group difference in CPM effect, suggesting that they were not driving the effects observed; hence, to be conservative, these were retained in the analysis.

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3.8. Exploratory correlational analyses

Consistent significant correlations were identified between male sex and PPTs outside of the lumbar region (R > 0.348, P < 0.01), cPDT (R > 0.282, P < 0.05), and cPTT (R > 0.522, P < 0.001) across both sessions. Pain area, both at rest and when moving, was also related to cPTT (R > 0.636, P < 0.001) among patients on day 0. All other correlations were insignificant, and none of the measured demographic, questionnaire, or clinical outcomes showed a significant association to variation in TSP or CPM.

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4. Discussion

This is the first study to assess nociceptive facilitation and inhibition in RLBP patients over painful and nonpainful periods. As hypothesised, patients in pain demonstrated reduced PPTs over both local and some distant sites, increased perceived painfulness of suprathreshold stimuli, and enhanced TSP compared with controls. Contrary to the hypothesis, however, these alterations were not maintained when RLBP patients were pain-free, with PPTs, suprathreshold ratings, and TSP not different to controls on day 28. Overall, RLBP patients displayed weaker CPM effects than controls across both sessions.

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4.1. Participant characteristics and clinical features

In this study, a subclinical RLBP population was investigated. No participants were actively seeking care, and all were expected to recover within the study timeframe. This contrasts the inclusion criteria of many previous studies, where lower limits are often set for pain and disability scores,1,55 and patients are expected to be sufficiently impacted by their pain to contact a health practitioner. This subclinical sample was of particular interest to gain insight into alterations and fluctuations in pain mechanistic measures before individuals becoming “pain patients,” because observed changes may be less influenced by comorbid ramifications, and more useful in identifying early intervention targets. Despite their subclinical status, the history and symptom presentation of these participants mirrored usual nonspecific LBP complaints.13

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4.2. Hyperalgesia to pressure

Participants with RLBP demonstrated hyperalgesia both locally at the lower back and at 2 distant sites both compared with themselves when pain-free, and to controls. Widespread hyperalgesia is purported to be a sign of facilitated central mechanisms4 and has been demonstrated previously in patients with acute30 and chronic46 LBP. However, the present findings suggest that this may be a state rather than trait feature consequential to or maintained by ongoing nociception and/or pain, at least in patients with RLBP, given the fact that it normalised by the second session. This is in line with studies showing normalisation of widespread hyperalgesia after temporary57 or permanent2,25 removal of peripheral nociceptive input, and with a previous study showing widespread hyperalgesia in the presence of experimental exercise-evoked LBP.38

During the painful episode, participants with RLBP also demonstrated lower cPDTs than when pain-free. This provides further support to PPT findings, by showing similar pressure hyperalgesia during pain compared with when pain-free, with a user-independent method to minimise bias from lack of blinding. However, these thresholds did not differ from controls during either session. Cuff pain detection values in the present control group seem lower than those reported previously in larger pain-free samples using the same methodology24 though, suggesting that the lack of group difference may be due to lower-than-normal control thresholds.

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4.3. Temporal summation of pain

Temporal summation of pain was observed in each group and session across repeated stimuli; however, the magnitude of this temporal increase in VAS scores was higher in participants with RLBP during their painful episode than both themselves when pain-free and controls. In addition, it was clear that the RLBP group generally rated suprathreshold stimuli to be more painful in the first session than in the second. Facilitated temporal summation is commonly observed in patients with current acute56,61 and chronic8,17,59 LBP, although previous effects in pain-free periods have not been well explored. A single pilot study37 following acute LBP patients over 4 months did, however, show tendencies somewhat in line with the present work, whereby those who developed persistent back pain showed trends toward higher facilitation (wind-up ratio) at follow-up than those who had recovered. As well, it is well known that experimentally provoked muscle pain can facilitate TSP locally over the affected muscle, compared with pain-free states.43,44

Taken together, these findings are consistent with the original concept of wind-up,63 suggesting that during a painful episode, ongoing peripheral nociceptive input drives enhanced spinal excitability, thus shifting the balance between inhibition and facilitation toward being more pronociceptive. However, other factors may also contribute, such as heightened vigilance toward painful sensations (supported by the higher PCS scores), such that all stimuli are generally perceived to be more salient and threatening when in clinical pain. This would fit with previous work in acute LBP, showing changes in pain-related fear and avoidance generally corresponding to exacerbation or reduction of pain.53 Nonetheless, TSP is a relative measure, meaning heightened vigilance should have less influence here than on absolute or threshold measures.

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4.4. Conditioned pain modulation

Larger overall CPM effects were observed in controls than in RLBP patients. Such findings of only weak overall effects are unsurprising in the context of the present literature, where reports of CPM efficacy in LBP patients are highly variable.50 Nevertheless, the small magnitude of difference here may be due to the relatively localised, low-intensity, low-disability pain that patients were experiencing. No relation between CPM and pain at the time of testing was observed here. However, previous studies have shown patients with more frequent, severe,22 and widespread18 LBP to have greater CPM impairment. It is also important to note that this impairment in CPM effect seemed to persist even in the absence of a painful episode. This could suggest that this mechanism may be impaired in these individuals even before the onset of pain. Alternatively, it could indicate a progressive degradation in CPM with continued or repeated painful experiences, which would be consistent with correlations between pain duration and CPM impairment demonstrated in other painful conditions.3

In the additional analysis (supplementary material, available at http://links.lww.com/PAIN/A862), for controls, there was a clear effect of conditioning on test stimuli, with both cuff pain detection and tolerance thresholds increased during and after conditioning. On the contrary, RLBP participants demonstrated significant inhibition only for pain tolerance during conditioning, but not at any point for PDTs. This is in line with previous work in acute LBP39 and migraine sufferers,40 where CPM effects have been present, but for shorter periods than controls. As well, the contrast between inhibitory effects on tolerance, but not detection thresholds, in RLBP patients is interesting. Pain detection may be more reflective of sensory factors and nociception, whereas pain tolerance has long been acknowledged to be more influenced by cognitive factors,16 and thus may be more amenable to inhibition through other supraspinal mechanisms.

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4.5. Implications of findings

Previous work has indicated that RLBP patients may show alterations in postural control34 and muscle structure,12 even in periods of recovery. However, the present findings indicate, somewhat on the contrary, that once the pain episode subsides, measures of pronociceptive pressure pain sensitivity return to levels comparable with pain-free individuals. This may be due to the mild RLBP condition in the present sample, such that over longer durations with higher frequencies or intensities of pain episodes, participants may progress toward a more permanent state of sensitisation. Alternatively, the present work could raise doubt over the significance of alterations in pronociceptive mechanisms observed in cross-sectional work because these differences may be consequential to the presence of ongoing nociception and pain. In line, these findings could provide some explanation for variation among previous studies, given that the presence of “pain flares” is not always considered in chronic LBP studies, despite recognition as a fluctuating condition.35,55

Notably, CPM was one variable in which a normalisation between sessions was not demonstrable, and only overall differences from controls were observed. Although interpretation of this impairment is limited by the weak effects observed and high measure variability, this suggests that impaired CPM may be an important contributor to LBP recurrence. Furthermore, because CPM is known to be impaired by poor sleep,54 aberrant physical activity,14,41 and increased psychosocial stress,19 factors also associated to LBP recurrence or persistence,30,52 it is conceivable that a constellation of symptoms on an already impaired pain inhibitory system may be enough to ignite a pain episode without obvious provocation. Causal relationships are, however, impossible to determine from the present work and thus this requires further investigation.

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4.6. Limitations

This study has several limitations requiring consideration. First, the order of sessions could not be randomized due to the unpredictable nature of RLBP combined with the decreasing reliability of psychophysical measures over longer intervals36; however, a control group was used to mitigate the influence of time and order on observed effects. Second, the study was sufficiently powered to detect moderate effect sizes, though may have been less powered to detect small differences. The sample, albeit purposely recruited this way, were young and well functioning despite pain, limiting generalisability to older and more severe populations. Finally, the assessor was not blinded to group; however, standardised instructions were given for all tests, care was taken to ensure consistent methodology, and several main outcomes were measured with user-independent equipment.

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4.7. Conclusion

This study reports, for the first time, local and distant hyperalgesia to handheld and cuff-induced pressure, as well as facilitated pronociceptive mechanisms, in participants with mild RLBP currently experiencing a painful episode, both compared to themselves when pain-free and compared to age and sex-matched controls. Conditioned pain modulation, as an antinociceptive mechanism, was generally lower in RLBP patients across sessions. Taken together, these findings indicate that enhanced pronociceptive measures in RLBP patients may be primarily consequential to the presence of pain, whereas impaired CPM may persist even in the absence of pain.

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Disclosures

The authors have no conflicts of interest to declare.

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Appendix A. Supplemental digital content

Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/A862.

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Supplemental video content

A video abstract accompanying this article can be found at http://links.lww.com/PAIN/A863.

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Acknowledgements

Center for Neuroplasticity and Pain (CNAP) is supported by the Danish National Research Foundation (DNRF121), and Nocitech is partly owned by Aalborg University. Associate Professor Shellie Boudreau and Algance Solutions are acknowledged for providing the Navigate Pain application for collection and presentation of pain distribution data.

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References

[1]. Amundsen PA, Evans DW, Rajendran D, Bright P, Bjorkli T, Eldridge S, Buchbinder R, Underwood M, Froud R. Inclusion and exclusion criteria used in non-specific low back pain trials: a review of randomised controlled trials published between 2006 and 2012. BMC Musculoskelet Disord 2018;19:113.
[2]. Aranda-Villalobos P, Fernandez-de-Las-Penas C, Navarro-Espigares JL, Hernandez-Torres E, Villalobos M, Arendt-Nielsen L, Arroyo-Morales M. Normalization of widespread pressure pain hypersensitivity after total hip replacement in patients with hip osteoarthritis is associated with clinical and functional improvements. Arthritis Rheum 2013;65:1262–70.
[3]. Arendt-Nielsen L, Egsgaard LL, Petersen KK, Eskehave TN, Graven-Nielsen T, Hoeck HC, Simonsen O. A mechanism-based pain sensitivity index to characterize knee osteoarthritis patients with different disease stages and pain levels. Eur J Pain 2015;19:1406–17.
[4]. Arendt-Nielsen L, Morlion B, Perrot S, Dahan A, Dickenson A, Kress HG, Wells C, Bouhassira D, Mohr Drewes A. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain 2018;22:216–41.
[5]. Arendt-Nielsen L, Sluka KA, Nie HL. Experimental muscle pain impairs descending inhibition. PAIN 2008;140:465–71.
[6]. Balaguier R, Madeleine P, Vuillerme N. Is one trial sufficient to obtain excellent pressure pain threshold reliability in the low back of asymptomatic individuals? A test-retest study. PLoS One 2016;11:e0160866.
[7]. Bishop MD, George SZ, Robinson ME. Dynamic, but not static, pain sensitivity predicts exercise-induced muscle pain: covariation of temporal sensory summation and pain intensity. Neurosci Lett 2012;526:1–4.
[8]. Biurrun Manresa JA, Neziri AY, Curatolo M, Arendt-Nielsen L, Andersen OK. Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain. PAIN 2013;154:1318–24.
[9]. Blumenstiel K, Gerhardt A, Rolke R, Bieber C, Tesarz J, Friederich HC, Eich W, Treede RD. Quantitative sensory testing profiles in chronic back pain are distinct from those in fibromyalgia. Clin J Pain 2011;27:682–90.
[10]. Cathcart S, Winefield AH, Rolan P, Lushington K. Reliability of temporal summation and diffuse noxious inhibitory control. Pain Res Manag 2009;14:433–8.
[11]. Correa JB, Costa LO, de Oliveira NT, Sluka KA, Liebano RE. Central sensitization and changes in conditioned pain modulation in people with chronic nonspecific low back pain: a case-control study. Exp Brain Res 2015;233:2391–9.
[12]. D'Hooge R, Cagnie B, Crombez G, Vanderstraeten G, Achten E, Danneels L. Lumbar muscle dysfunction during remission of unilateral recurrent nonspecific low-back pain: evaluation with muscle functional MRI. Clin J Pain 2013;29:187–94.
[13]. Delitto A, George SZ, Van Dillen LR, Whitman JM, Sowa G, Shekelle P, Denninger TR, Godges JJ. Orthopaedic section of the American Physical Therapy A: low back pain. J Orthop Sports Phys Ther 2012;42:A1–57.
[14]. Ellingson LD, Shields MR, Stegner AJ, Cook DB. Physical activity, sustained sedentary behavior, and pain modulation in women with fibromyalgia. J Pain 2012;13:195–206.
[15]. Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin 2006;22:1911–20.
[16]. Gelfand S. The relationship of experimental pain tolerance to pain threshold. Can J Psychol 1964;18:36–42.
[17]. Gerhardt A, Eich W, Janke S, Leisner S, Treede RD, Tesarz J. Chronic widespread back pain is distinct from chronic local back pain. Clin J Pain 2016;32:568–79.
[18]. Gerhardt A, Eich W, Treede RD, Tesarz J. Conditioned pain modulation in patients with nonspecific chronic back pain with chronic local pain, chronic widespread pain, and fibromyalgia. PAIN 2017;158:430–9.
[19]. Geva N, Pruessner J, Defrin R. Acute psychosocial stress reduces pain modulation capabilities in healthy men. PAIN 2014;155:2418–25.
[20]. Giesecke T, Gracely RH, Grant MA, Nachemson A, Petzke F, Williams DA, Clauw DJ. Evidence of augmented central pain processing in idiopathic chronic low back pain. Arthritis Rheum 2004;50:613–23.
[21]. Goubert D, Danneels L, Cagnie B, Van Oosterwijck J, Kolba K, Noyez H, Meeus M. Effect of pain induction or pain reduction on conditioned pain modulation in adults: a systematic review. Pain Pract 2015;15:765–77.
[22]. Goubert D, Danneels L, Graven-Nielsen T, Descheemaeker F, Meeus M. Differences in pain processing between patients with chronic low back pain, recurrent low back pain, and fibromyalgia. Pain Physician 2017;20:307–18.
[23]. Graven-Nielsen T, Izumi M, Petersen KK, Arendt-Nielsen L. User-independent assessment of conditioning pain modulation by cuff pressure algometry. Eur J Pain 2017;21:552–61.
[24]. Graven-Nielsen T, Vaegter HB, Finocchietti S, Handberg G, Arendt-Nielsen L. Assessment of musculoskeletal pain sensitivity and temporal summation by cuff pressure algometry: a reliability study. PAIN 2015;156:2193–202.
[25]. Graven-Nielsen T, Wodehouse T, Langford RM, Arendt-Nielsen L, Kidd BL. Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum 2012;64:2907–16.
[26]. Hallal PC, Victora CG. Reliability and validity of the International Physical Activity Questionnaire (IPAQ). Med Sci Sports Exerc 2004;36:556.
[27]. Hirshkowitz M, Whiton K, Albert SM, Alessi C, Bruni O, DonCarlos L, Hazen N, Herman J, Katz ES, Kheirandish-Gozal L, Neubauer DN, O'Donnell AE, Ohayon M, Peever J, Rawding R, Sachdeva RC, Setters B, Vitiello MV, Ware JC, Adams Hillard PJ. National Sleep Foundation's sleep time duration recommendations: methodology and results summary. Sleep Health 2015;1:40–3.
[28]. Hubscher M, Moloney N, Leaver A, Rebbeck T, McAuley JH, Refshauge KM. Relationship between quantitative sensory testing and pain or disability in people with spinal pain-a systematic review and meta-analysis. PAIN 2013;154:1497–504.
[29]. Kennedy DL, Kemp HI, Ridout D, Yarnitsky D, Rice AS. Reliability of conditioned pain modulation: a systematic review. PAIN 2016;157:2410–19.
[30]. Klyne DM, Moseley GL, Sterling M, Barbe MF, Hodges PW. Individual variation in pain sensitivity and conditioned pain modulation in acute low back pain: effect of stimulus type, sleep, and psychological and lifestyle factors. J Pain 2018;19:942.e941–942.e918.
[31]. Ladouceur A, Rustamov N, Dubois JD, Tessier J, Lehmann A, Descarreaux M, Rainville P, Piche M. Inhibition of pain and pain-related brain activity by heterotopic noxious counter-stimulation and selective attention in chronic non-specific low back pain. Neuroscience 2018;387:201–13.
[32]. Lewis GN, Rice DA, McNair PJ. Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis. J Pain 2012;13:936–44.
[33]. Lorish CD, Maisiak R. The Face Scale: a brief, nonverbal method for assessing patient mood. Arthritis Rheum 1986;29:906–9.
[34]. MacDonald D, Moseley GL, Hodges PW. People with recurrent low back pain respond differently to trunk loading despite remission from symptoms. Spine (Phila Pa 1976) 2010;35:818–24.
[35]. Macedo LG, Maher CG, Latimer J, McAuley JH, Hodges PW, Rogers WT. Nature and determinants of the course of chronic low back pain over a 12-month period: a cluster analysis. Phys Ther 2014;94:210–21.
[36]. Marcuzzi A, Wrigley PJ, Dean CM, Adams R, Hush JM. The long-term reliability of static and dynamic quantitative sensory testing in healthy individuals. PAIN 2017;158:1217–23.
[37]. Marcuzzi A, Wrigley PJ, Dean CM, Graham PL, Hush JM. From acute to persistent low back pain: a longitudinal investigation of somatosensory changes using quantitative sensory testing-an exploratory study. Pain Rep 2018;3:e641.
[38]. McPhee M, Graven-Nielsen T. Alterations in temporal summation of pain and conditioned pain modulation across an episode of experimental exercise-induced low back pain. J Pain 2018;20:264–76.
[39]. Mlekusch S, Neziri AY, Limacher A, Juni P, Arendt-Nielsen L, Curatolo M. Conditioned pain modulation in patients with acute and chronic low back pain. Clin J Pain 2016;32:116–21.
[40]. Nahman-Averbuch H, Granovsky Y, Coghill RC, Yarnitsky D, Sprecher E, Weissman-Fogel I. Waning of “conditioned pain modulation”: a novel expression of subtle pronociception in migraine. Headache 2013;53:1104–15.
[41]. Naugle KM, Riley JL III. Self-reported physical activity predicts pain inhibitory and facilitatory function. Med Sci Sports Exerc 2014;46:622–9.
[42]. Neziri AY, Curatolo M, Limacher A, Nuesch E, Radanov B, Andersen OK, Arendt-Nielsen L, Juni P. Ranking of parameters of pain hypersensitivity according to their discriminative ability in chronic low back pain. PAIN 2012;153:2083–91.
[43]. Nie H, Arendt-Nielsen L, Madeleine P, Graven-Nielsen T. Enhanced temporal summation of pressure pain in the trapezius muscle after delayed onset muscle soreness. Exp Brain Res 2006;170:182–90.
[44]. Nie H, Madeleine P, Arendt-Nielsen L, Graven-Nielsen T. Temporal summation of pressure pain during muscle hyperalgesia evoked by nerve growth factor and eccentric contractions. Eur J Pain 2009;13:704–10.
[45]. O'Brien AT, Deitos A, Trinanes Pego Y, Fregni F, Carrillo-de-la-Pena MT. Defective endogenous pain modulation in fibromyalgia: a meta-analysis of temporal summation and conditioned pain modulation paradigms. J Pain 2018;19:819–36.
[46]. O'Neill S, Manniche C, Graven-Nielsen T, Arendt-Nielsen L. Generalized deep-tissue hyperalgesia in patients with chronic low-back pain. Eur J Pain 2007;11:415–20.
[47]. Petersen KK, Simonsen O, Laursen MB, Arendt-Nielsen L. The role of preoperative radiologic severity, sensory testing, and temporal summation on chronic postoperative pain following total knee arthroplasty. Clin J Pain 2018;34:193–7.
[48]. Puta C, Schulz B, Schoeler S, Magerl W, Gabriel B, Gabriel HH, Miltner WH, Weiss T. Enhanced sensitivity to punctate painful stimuli in female patients with chronic low back pain. BMC Neurol 2012;12:98.
[49]. Roland M, Morris R. A study of the natural-history of back pain. 1. Development of a reliable and sensitive measure of disability in low-back-pain. Spine 1983;8:141–4.
[50]. Roussel NA, Nijs J, Meeus M, Mylius V, Fayt C, Oostendorp R. Central sensitization and altered central pain processing in chronic low back pain: fact or myth? Clin J Pain 2013;29:625–38.
[51]. Shahidi B, Maluf KS. Adaptations in evoked pain sensitivity and conditioned pain modulation after development of chronic neck pain. Biomed Res Int 2017;2017:8985398.
[52]. Shiri R, Falah-Hassani K. Does leisure time physical activity protect against low back pain? Systematic review and meta-analysis of 36 prospective cohort studies. Br J Sports Med 2017;51:1410–18.
[53]. Sieben JM, Vlaeyen JWS, Tuerlinckx S, Portegijs PJM. Pain-related fear in acute low back pain: the first two weeks of a new episode. Eur J Pain 2002;6:229–37.
[54]. Smith MT, Edwards RR, McCann UD, Haythornthwaite JA. The effects of sleep deprivation on pain inhibition and spontaneous pain in women. Sleep 2007;30:494–505.
[55]. Stanton TR, Latimer J, Maher CG, Hancock MJ. How do we define the condition “recurrent low back pain”? A systematic review. Eur Spine J 2010;19:533–9.
[56]. Starkweather AR, Ramesh D, Lyon DE, Siangphoe U, Deng X, Sturgill J, Heineman A, Elswick RK, Dorsey SG, Greenspan J. Acute low back pain: differential somatosensory function and gene expression compared with healthy no-pain controls. Clin J Pain 2016;32:933–9.
[57]. Staud R, Weyl EE, Bartley E, Price DD, Robinson ME. Analgesic and anti-hyperalgesic effects of muscle injections with lidocaine or saline in patients with fibromyalgia syndrome. Eur J Pain 2014;18:803–12.
[58]. Sullivan MJL, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychol Assess 1995;7:524–32.
[59]. Tesarz J, Eich W, Treede RD, Gerhardt A. Altered pressure pain thresholds and increased wind-up in adult patients with chronic back pain with a history of childhood maltreatment: a quantitative sensory testing study. PAIN 2016;157:1799–809.
[60]. Tschugg A, Loscher WN, Hartmann S, Neururer S, Wildauer M, Thome C. Gender influences radicular pain perception in patients with lumbar disc herniation. J Womens Health 2015;24:771–6.
[61]. Vuilleumier PH, Arguissain FG, Biurrun Manresa JA, Neziri AY, Nirkko AC, Andersen OK, Arendt-Nielsen L, Curatolo M. Psychophysical and electrophysiological evidence for enhanced pain facilitation and unaltered pain inhibition in acute low back pain patients. J Pain 2017;18:1313–23.
[62]. Waller R, Straker L, O'Sullivan P, Sterling M, Smith A. Reliability of pressure pain threshold testing in healthy pain free young adults. Scand J Pain 2015;9:38–41.
[63]. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. PAIN 2011;152(3 suppl):S2–15.
[64]. Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, Ben-Nun A, Sprecher E, Best LA, Granot M. Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. PAIN 2008;138:22–8.
Keywords:

Conditioned pain modulation; Temporal summation of pain; Pain mechanisms; Recurrent low back pain; Pressure pain thresholds; Longitudinal case-control study

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