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Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain
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PAIN 154 (2013) 1318–1324
www.elsevier.com/locate/pain
Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain José A. Biurrun Manresa a,⇑,1, Alban Y. Neziri b,c,1, Michele Curatolo b, Lars Arendt-Nielsen a, Ole K. Andersen a a b c
Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 7, 9220 Aalborg Øst, Denmark University Department of Anesthesiology and Pain Therapy, University Hospital of Bern, Inselspital, Freiburgstrasse, 3010 Bern, Switzerland Department of Obstetrics and Gynaecology, Cantonal Hospital of St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
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Article history: Received 13 November 2012 Received in revised form 12 March 2013 Accepted 3 April 2013
Keywords: Central hyperexcitability Low back pain Neck pain Nociceptive withdrawal reflex Pain hypersensitivity Reflex receptive field
a b s t r a c t Pain hypersensitivity has been consistently detected in chronic pain conditions, but the underlying mechanisms are difficult to investigate in humans and thus poorly understood. Patients with endometriosis pain display enlarged reflex receptive fields (RRF), providing a new perspective in the identification of possible mechanisms behind hypersensitivity states in humans. The primary hypothesis of this study was that RRF are enlarged in patients with musculoskeletal pain. Secondary study end points were subjective pain thresholds and nociceptive withdrawal reflex (NWR) thresholds after single and repeated (temporal summation) electrical stimulation. Forty chronic neck pain patients, 40 chronic low back pain patients, and 24 acute low back pain patients were tested. Electrical stimuli were applied to 10 sites on the sole of the foot to quantify the RRF, defined as the area of the foot from where a reflex was evoked. For the secondary end points, electrical stimuli were applied to the cutaneous innervation area of the sural nerve. All patient groups presented enlarged RRF areas compared to pain-free volunteers (P < .001). Moreover, they also displayed lower NWR and pain thresholds to single and repeated electrical stimulation (P < .001). These results demonstrate that musculoskeletal pain conditions are characterized by enlarged RRF, lowered NWR and pain thresholds, and facilitated temporal summation, most likely caused by widespread spinal hyperexcitability. This study contributes to a better understanding of the mechanisms underlying these pain conditions, and it supports the use of the RRF and NWR as objective biomarkers for pain hypersensitivity in clinical and experimental pain research. Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Pain hypersensitivity is an expression of neuronal plasticity that causes an amplification of the pain sensation, which depends on specific patterns of activation, modulation, or modification of the nociceptive input [46]. It is usually characterized as a state of hyperexcitability of the central nervous system and changes in endogenous pain modulation, resulting in painful perceptions to normally innocuous stimuli (allodynia) or to exaggerated responses to painful stimuli (hyperalgesia). The mechanisms also include facilitated temporal summation and enlargement of the referred pain areas. These alterations are commonly present in chronic musculoskeletal conditions [20], and they are likely relevant from a clinical perspective, as they influence the magnitude ⇑ Corresponding author. Tel.: +45 9940 8715; fax: +45 9815 4008. 1
E-mail address: [email protected] (J.A. Biurrun Manresa). These authors contributed equally to this work.
of pain and disability [12]. Although pain hypersensitivity has been consistently detected in chronic pain, the underlying mechanisms are difficult to investigate in humans and therefore poorly understood. The assessment of the underlying central mechanisms behind pain hypersensitivity in humans is a challenging task because direct neural recording is not possible. Instead, a series of psychophysical quantitative sensory tests are usually performed in order to assess a characteristic constellation of sensory signs and symptoms that can be associated with hypersensitivity [34,46]. The rationale behind these tests is that pain hypersensitivity detected after stimulation of healthy tissue has to be a consequence of alterations in central processing [12]. The use of quantitative sensory tests has brought great advancement in the field of pain research; however, they are bounded by inherent limitations, such as their subjective nature, allowing them to be biased, modulated, or influenced by factors not necessarily influencing the central nociceptive processing [43].
0304-3959/$36.00 Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.pain.2013.04.013
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Electrophysiological tests can also be used to assess nociceptive hyperexcitability. In particular, tests based on the nociceptive withdrawal reflex (NWR) and reflex receptive fields (RRF) display some advantages over psychophysical assessments. In the first place, they are objective, in the sense that the outcome of the test does not directly rely on conscious decisions from the researcher/ physician or the subject/patient under controlled experimental conditions. They have demonstrated high reliability when performed in healthy volunteers [23,32] as well as in patients with painful conditions [7]. More importantly, they also provide some insight into the location and mechanisms behind the alterations, revealing that at least part of the hypersensitivity is the result of spinal hyperexcitability [14,41]. In relation to this, a recent investigation revealed that patients with endometriosis pain display enlarged RRF [29], thus opening a new perspective in the identification of possible mechanisms underlying hypersensitivity states in humans. The primary aim of the present study was to test the hypothesis that RRF are enlarged in patients with acute and chronic musculoskeletal pain conditions compared to healthy volunteers. Additionally, NWR and pain thresholds after single and repeated electrical stimulation of the sural nerve were analyzed in order to test subjective pain sensitivity, facilitated temporal summation, and spinal excitability. The results were expected to provide insights into the mechanisms underlying chronic musculoskeletal pain and to offer a perspective to identify potential biomarkers for the objective assessment of central hyperexcitability in humans.
2. Materials and methods 2.1. Participants 2.1.1. Patients Patients were recruited at the Department of Anaesthesiology and Pain Therapy of the University Hospital of Bern, Inselspital. Forty patients with chronic neck pain, 40 patients with chronic low back pain, and 24 patients with acute low back pain participated in the study. The patients with chronic low back pain were part of a case-control study that was recently published [27]. Inclusion criteria for chronic pain patients were daily pain of at least 6 months’ duration and pain at the time of testing with an intensity of at least 3 on a 10-cm visual analog scale, with 0 indicating no pain and 10 the worst pain imaginable. Inclusion criteria for acute pain patients were daily pain for no longer than 4 weeks, no history of chronic low back pain, and pain at the time of testing with an intensity of at least 3 on a 10-cm visual analog scale, with 0 indicating no pain and 10 the worst pain imaginable. Exclusion criteria were radicular pain (as defined by leg pain associated with a magnetic resonance imaging finding of herniated disc or foraminal stenosis with contact to a nerve root), peripheral or central neurological disorders, diabetes mellitus, insufficient knowledge of the German language, pregnancy (as excluded by a pregnancy test), breast-feeding, intake of oral contraceptives or hormones, intake of opioids and antidepressants during the previous 2 weeks, and intake of other analgesics during the 48 h before testing. All subjects provided written informed consent before participating. The study protocol was approved by the local ethics committee of the Canton of Bern, and the study was performed in accordance with the Declaration of Helsinki.
2.1.2. Pain-free subjects The control group consisted of 300 pain-free subjects who had been recently analyzed to determine the reference values of the reflex parameters in the pain-free population [25]. Exclusion criteria
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were the same as for the patient group, plus the following: any pain at the time of testing or history of chronic pain syndrome of any nature. 2.2. Descriptive variables To provide comprehensive information about the patient population, several descriptive variables were recorded, including gender, age, height, weight, and body mass index, pain intensity at the time of testing, and maximum pain intensity ever experienced. Volunteers were also asked to complete the following questionnaires: Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), and Catastrophizing Scale of the Coping Strategies Questionnaire (CSQ). A thorough description of the questionnaires is provided by Neziri et al. [29]. 2.3. Electrophysiological and psychophysical pain tests The main end point according to the study hypothesis was the assessment of RRF. Secondary end points were subjective pain thresholds and parameters of spinal cord nociceptive excitability, namely NWR thresholds to single and repeated electrical stimulation. All the experiments were performed by the same investigator (AN). During the testing session, the volunteers were lying in a bed in a quiet room. A leg rest was placed under the knee to obtain a 10° flexion. Each subject underwent a training session for all tests in order to get familiar with the stimulation procedures before starting the data collection. Tests for RRF, single electrical stimulation, and repeated electrical stimulation were performed in a randomized order. All the tests were applied to the same body side within each subject, with the side being selected randomly by the investigator in a ratio of 1:1. 2.3.1. RRF assessment [26] have previously described a detailed procedure to assess the RRF. In short, 10 surface electrodes (15 15 mm, type 700, Ambu A/S, Denmark) were mounted on the sole of the foot, and a common anode (50 90 mm electrode, type Synapse, Ambu A/S, Denmark) was placed on the dorsum of the foot. Each stimulus consisted of a constant current pulse train of 5 individual 1-ms pulses delivered at 200 Hz (Stimulator Noxitest IES 230, Aalborg University, Denmark), felt as a single stimulus. The current intensity was increased from 1 mA in steps of 0.5 mA as the pain sensation was evoked (pain threshold) for each of the 10 stimulation sites. To avoid the subjects’ gradual adaptation to the stimulus while determining the pain thresholds at the different sites, the identified pain threshold at the arch of the foot was repeatedly presented to the volunteer for reference. After all pain thresholds were determined, a stimulus with an intensity equal to that 1.5 times higher than the individual pain threshold was delivered 4 times to each individual site, for a total of 40 stimulations. A computercontrolled electrical relay delivered the stimulus to 1 of the 10 electrodes in a randomized sequence at random time intervals (between 8 and 12 s), so that the subject was not aware of when the stimulus was applied. The NWR was measured by surface electromyographic (EMG) electrodes (type 720, Ambu A/S, Denmark) over the belly of the tibialis anterior muscle (interelectrode distance of 2 cm) because the expected biomechanical response to stimulation of the sole of the foot is primarily ankle dorsiflexion [2]. The EMG signals were amplified (up to 50,000 times), filtered (5–500 Hz, second order), sampled (2000 Hz), displayed on the computer screen, and stored on a computer disk. The EMG signals were recorded from 200 ms before stimulation until 1000 ms after stimulation onset. EMG reflex responses were quantified using root– mean–square (RMS) amplitude in the 60–180-ms poststimulation
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interval. RRF sensitivity maps were derived by 2-dimensional interpolation of the RMS amplitudes. RRF sensitivity areas were calculated as the fraction of the sole of the foot delimited by a threshold set by the peak RMS amplitude minus 2 times the standard deviation of the remaining RMS amplitudes. 2.3.2. Thresholds to single electrical stimulation Electrical stimulation was performed through surface electrodes placed caudal to the lateral malleolus, at the innervation area of the sural nerve [5]. The same train of five 1-ms square wave pulses delivered at 200 Hz was used. EMG reflex responses to electrical stimulation were recorded from the belly of the biceps femoris and the rectus femoris muscles by surface electrodes (type 720, Ambu A/S, Denmark) because the expected biomechanical response to stimulation of the sural nerve is primarily knee–hip flexion [2,5]. The current intensity was increased from 1 mA in steps of 0.5 mA until: (1) a reflex with an amplitude exceeding 20 lV for at least 10 ms in the 60–180-ms poststimulation interval was detected (single stimulus NWR threshold); and (2) a pain sensation was evoked (single stimulus pain threshold). These procedures were repeated 3 times, and the median value was used as the respective thresholds. 2.3.3. Thresholds to repeated electrical stimulation (temporal summation) The stimulus burst used for single stimulus was repeated 5 times at a frequency of 2 Hz and at constant stimulus intensity [3]. EMG recordings were similar as for single stimulation. The current intensity of the 5 constant stimuli was increased from 1 mA in steps of 0.5 mA until: (1) an increase in the amplitude of the last 1– 3 reflexes above a fixed limit of 20 lV for at least 10 ms in the 70– 150-ms poststimulation interval was observed (temporal summation NWR threshold); and (2) the subjects felt pain during the last 1–3 of the 5 electrical bursts (temporal summation pain threshold). These procedures were repeated 3 times, and the median value was used as the respective thresholds. 2.4. Data analysis 2.4.1. Sample size considerations In agreement with previous studies [29], it was established that a significant difference of 0.144 in RRF area among groups would be detected by a sample size of 17 subjects per group. To minimize the likelihood of insufficient power due to unexpected higher variability, it was decided to study at least 24 patients per group. Therefore, consecutive patients were recruited until all the groups reached the minimum size of 24 patients. 2.4.2. Statistical analyses Descriptive variables (demographic, psychological, and health related) and quantitative variables derived from electrophysiological and psychophysical pain tests (RRF areas, NWR, and pain thresholds) between groups were compared by the Kruskall-Wallis test (for nonnormally distributed data). Post hoc pairwise comparisons were performed by the Wilcoxon test. P values of <.05 were considered significant. In order to study the independent contribution of psychological factors, multiple linear regression analyses were conducted on each test, ie, RRF area, pain, and reflex thresholds to single and repeated electrical stimulation. In all 5 regressions, the following independent (explanatory) variables were analyzed: group (patients or controls), BDI, STAI-State and CSQ catastrophizing (STAI-Trait was excluded as a result of collinearity with STAI-State). All values are presented as median (25% quartile– 75% quartile).
3. Results 3.1. Descriptive variables The statistical analysis of descriptive variables from the different groups is presented in Table 1. Among the demographic variables, height and body mass index presented a statistically significant difference among groups (Kruskall-Wallis, P = .007 and P = .012, respectively), although it does not seem to bear any relevance in relation to the quantitative variables derived from the electrophysiological and psychophysical tests. On the other hand, patients presented statistically significant higher scores in all psychological variables (BDI, STAI-State, STAI-Trait, and CSQ catastrophizing) compared to controls (Wilcoxon, all P values <.001), with the exception of CSQ catastrophizing scores between acute low back pain patients and controls (Wilcoxon, P = .879). Moreover, there were also differences between acute and chronic pain patients. BDI, STAI-Trait, and CSQ catastrophizing scores were significantly lower in acute low back pain patients compared to chronic low back pain and chronic neck pain patients (Wilcoxon, P values ranging from <.001 to .005), whereas STAI-State scores were significantly lower in acute low back pain patients than in chronic neck pain patients (Wilcoxon, P = .047), but they were not significantly different from chronic low back pain patients scores (Wilcoxon, P = .129). 3.2. Electrophysiological and psychophysical pain tests The statistical analysis of quantitative variables derived from electrophysiological and psychophysical pain tests (RRF area, NWR and pain thresholds to single and repeated stimulation) is presented in Table 2 and illustrated in Figs. 1 and 2. All quantitative variables presented statistically significant differences between groups (Kruskall-Wallis, P < .001 for all tests). Post hoc pairwise comparisons revealed statistically significant differences between patients and controls; specifically, patients presented larger RRF areas (Wilcoxon, P values ranging from .001 to .047), lower single stimulation pain thresholds (Wilcoxon, all P values <.001), lower single stimulation NWR thresholds (Wilcoxon, all P values <.001), lower temporal summation pain thresholds (Wilcoxon, all P values <.001), and lower temporal summation NWR thresholds (Wilcoxon, P values ranging from <.001 to .013). Furthermore, chronic neck pain patients displayed lower single stimulation NWR thresholds (Wilcoxon, P = .033) and lower temporal summation pain thresholds (Wilcoxon, P = .017) compared to acute low back pain patients. 3.3. Multiple linear regression The results of the multiple linear regression analysis demonstrated that the predictors selected for accounted for 5% to 31% of the variance of the quantitative variables derived from electrophysiological and psychophysical pain tests (Table 3). In all cases, group was a statistically significant predictor (P < .001). Moreover, none of the psychological factors was significantly related to these variables, with the exception of STAI-State for single stimulation pain threshold (P = .016).
4. Discussion The main results of this study demonstrated that all patient groups with musculoskeletal pain conditions presented enlarged RRF areas compared to pain-free volunteers. Moreover, all patients displayed lower NWR and pain thresholds to single and repeated electrical stimulation compared to healthy subjects. Additionally,
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J.A. Biurrun Manresa et al. / PAIN 154 (2013) 1318–1324 Table 1 Demographic and psychological variables of the study population.a Characteristic
Chronic neck pain (n = 40)
Chronic low back pain (n = 40)
Acute low back pain (n = 23)
Controls (n = 300)
P
Age, y Height, cm Weight, kg BMI, kg/m2 Posttraumatic onset of pain Pain duration Current pain intensity rating, VAS Highest pain intensity rating, VAS BDI, score 0–63 STAI-State, score 20–80 STAI-Trait, score 20–80 CSQ catastrophizing, score 0–6
49 (42–62) 168 (163–175) 70 (64–80) 24.8 (22.3–27.6) 20 (50%) 51.0 (24.0–66.8) 5.4 (4.6–6.7) 9.0 (8.0–9.6) 10 (7–17) 58 (48–69) 56 (48–69) 3.0 (2.0–4.2)
50 (40–60) 172 (164–178) 74 (68–85) 25.7 (23.2–27.7) 0 (0%) 48.0 (13.8–111.0) 4.6 (4.2–5.8) 9.0 (8.3–10.0) 11 (7–17) 54 (46–65) 57 (48–69) 3.2 (2.2–4.2)
39 (30–54) 176 (168–185) 72 (68–84) 23.6 (21.7–25.6) 0 (%) 1.0 (1.0–2.5) 5.0 (4.0–6.0) 7.0 (6.0–8.0) 4 (2–8) 50 (46–55) 46 (41–54) 2.0 (1.2–2.7)
49 (34–65) 174 (168–180) 73 (63–85) 23.6 (21.9–26.3) NA NA NA NA 1 (0–4) 44 (41–47) 41 (38–46) 1.8 (1.3–2.6)
.071 .007** .587 .012* NA NA NA NA <.001*** <.001*** <.001*** <.001***
VAS, visual analog scale; BMI, body mass index; BDI, Beck Depression Inventory; STAI, State-Trait Anxiety Inventory; CSQ, Coping Strategies Questionnaire; NA, not applicable. a Numerical variables are presented as median (25% quartile–75% quartile). Categorical variables are presented as number of subjects in each group (percentage in relation to the group). Pain duration is expressed in months for chronic pain patients and in weeks for acute pain patients. * P < .05. ** P < .01. *** P < .001.
Table 2 Reflex receptive field areas and NWR and pain thresholds after single and repeated electrical stimulation.a Characteristic
Chronic neck pain patients (n = 40)
Chronic low back pain patients (n = 40)
Acute low back pain patients (n = 24)
Controls (n = 300)
P
Reflex receptive field area, fraction of the foot sole Single stimulation pain threshold, mA Single stimulation NWR threshold, mA Temporal summation pain threshold, mA Temporal summation NWR threshold, mA
0.40 (0.29–0.48) 6.2 (5.3–8.0) 9.3 (7.3–12.6) 5.0 (4.0–6.5) 5.6 (5.0–8.0)
0.39 (0.26–0.55) 6.8 (5.3–8.9) 10.3 (7.3–14.7) 6.0 (4.0–7.0) 7.0 (5.1–8.7)
0.46 (0.32–0.56) 8.0 (6.0–10.0) 12.0 (10.0–14.3) 7.0 (5.7–8.0) 7.0 (5.7–8.7)
0.30 (0.18–0.44) 11.0 (9.0–12.0) 16.0 (14.0–18.0) 8.3 (7.0–9.7) 8.3 (7.0–9.7)
<.001*** <.001*** <.001*** <.001*** <.001***
NWR, nociceptive withdrawal reflex. a Numerical variables are presented as median (25% quartile–75% quartile). *** P < .001.
chronic neck pain patients displayed lower single stimulation NWR thresholds and lower temporal summation pain thresholds compared to acute low back pain patients. These findings suggest that plasticity changes may lead to expansion of neuronal receptive fields or increased responsiveness of spinal neurons and facilitated temporal summation, which are likely important determinants of pain amplification. Accordingly, these assessment methods can be used as objective biomarkers of alterations in nociceptive processes in human musculoskeletal pain. 4.1. Assessment of pain hypersensitivity Pain hypersensitivity can be assessed by several different experimental tests: verbal reports, pain questionnaires, light touch, and vibration, as well as detection, first pain, and tolerance thresholds to pressure, electrical, heat, and cold stimuli [13,21,24,31,38–40]. In a recent study that ranked these tests according to their discriminative ability in chronic low back pain patients, pressure and electrical pain modalities demonstrated the most promising results [27]. However, the perception of pain is a complex multisensory experience, and different modalities assessed simultaneously are likely to provide a more complete representation of the nociception and pain experience [28]. In any case, most of the aforementioned methods used to assess pain hypersensitivity in humans rely on volunteer reports after sensory stimulation, which are subjective in nature. As such, they can be voluntarily and/or involuntarily affected by a number of factors, including the psychological distress associated with chronic pain conditions [10,22]. Nowadays, there is increasing evidence that objective methods, such as those based on the NWR and the RRF, can detect hyperexcitability in the nociceptive pathways
without the setbacks usually associated with subjective assessments. Indeed, measures derived from the NWR and the RRF are reliable [7,23,32] and stable against habituation [6] or other biasing factors, including psychological factors such as anxiety, depression, mental health, or pain catastrophizing [30]. The results of this study also demonstrated marked differences between patients and pain-free subjects; specifically, all patient groups displayed lower NWR and pain thresholds and larger RRF areas (Table 2). Several differences were also found in the psychological descriptors between these groups (Table 1), although in most cases these differences were not correlated with the outcome variables from the electrophysiological and psychophysical tests (Table 3). A single exception was found for single stimulation pain thresholds, which were correlated to anxiety state. This is in line with previous studies investigating the effect of anxiety on pain tests, in which subjective pain reports (such as electrical pain thresholds), but not objective measures (NWR thresholds and RRF areas), may be influenced by anxiety under standard testing conditions [17,30,44]. In general terms, none of the psychological factors are good predictors for changes in the quantification variables (RRF areas, NWR and pain thresholds), so this is an indication that the differences found in the pain tests are not likely related to disparities in psychological profiles among groups. 4.2. Mechanisms of pain hypersensitivity Pain hypersensitivity is characterized by dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, enhanced temporal summation, and enlargement of referred pain areas [20,45]. Experimental and clinical studies in diverse cohorts of patients (eg, whiplash, fibromyalgia, osteoarthritis,
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Fig. 1. Pain (left) and NWR (right) thresholds for single (top) and repeated (bottom) electrical stimulation. Data are presented as median, 10th, 25th, 75th, and 90th percentiles. Black dots represent the values that lie outside the 10th and 90th percentiles. NWR, nociceptive withdrawal reflex; CNP, chronic neck pain; CLBP, chronic low back pain; ALBP, acute low back pain; CTRL, control. ⁄P < .05; ⁄⁄⁄P < .001.
Fig. 2. Reflex receptive field areas, expressed as a fraction of the sole of the foot from which a reflex in the tibialis anterior muscle was elicited. Data are presented as median, 10th, 25th, 75th, and 90th percentiles. Black dots represent the values that lie outside the 10th and 90th percentiles. CNP, chronic neck pain; CLBP, chronic low back pain; ALBP, acute low back pain; CTRL, control. ⁄P < .05, ⁄⁄P < .01.
musculoskeletal disorders, headache, and neuropathic, visceral, and postsurgical pain) have demonstrated common features that are likely to reflect alterations in central pain processing [12,45]. It has been previously demonstrated that chronic pain due to endometriosis is associated with larger RRF areas compared to pain-free subjects [29]. Clearly, observations in a specific visceral pain condition are not necessarily applicable to other chronic pain conditions.
The main finding of the present study was that RRF areas were enlarged in patients with musculoskeletal pain compared to painfree volunteers. (The grand mean RRF areas for each group can be seen in Fig. 3.) The enlargement of RRF would indicate that spinal hyperexcitability could be a consequence of increased number of responsive spinal neurons or an expansion of the receptive fields of spinal neurons as a result of increased synaptic sensitivity [11,15]. In both cases, the RRF expansion was detected in areas distant from the site of expected tissue damage, indicating widespread spinal hyperexcitability [4,39]. Animal experiments indicate that humoral factors and/or alterations in the descending modulatory system may be at least partially responsible for this behavior [35,42,47], although the current evidence in humans does not allow to make a precise description of the mechanisms behind these phenomena [8,9,16,18,37]. Both acute and chronic pain patients displayed lower NWR thresholds after a single electrical stimulation compared to painfree volunteers. Moreover, temporal summation mechanisms were also altered in patients because NWR thresholds were also significantly lower after repeated electrical stimulation. These results are consistent with previous studies including patients with different clinical conditions, such as whiplash, fibromyalgia, and endometriosis [5,14,29]. Together, these results can be interpreted as electrophysiological evidence for central spinal hyperexcitability in these patient groups. Interestingly, the assessment of NWR and pain thresholds resulted in a graded outcome, in which it was possible to discriminate between pain-free volunteers and acute pain patients, but in
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J.A. Biurrun Manresa et al. / PAIN 154 (2013) 1318–1324 Table 3 Multiple regression analysis for quantitative variables derived from electrophysiological and psychophysical pain tests. Characteristic
SE
P
0.054 0.002 9.7e 6 0.005
0.013 0.002 0.001 0.012
<.001*** .365 .994 .574
Single stimulation pain threshold Group (control) BDI STAI-State CSQ catastrophizing R2 = 0.309, SEE = 2.471
1.504 0.003 0.049 0.078
0.180 0.032 0.020 0.141
<.001*** .920 .016* .584
Single stimulation NWR threshold Group (patients–control) BDI STAI-State CSQ catastrophizing R2 = 0.294, SEE = 3.732
2.315 0.001 0.046 0.073
0.273 0.049 0.030 0.215
<.001*** .778 .127 .733
Temporal summation pain threshold Group (patients–control) 1.085 BDI 0.020 STAI-State 0.011 CSQ catastrophizing 0.030 R2 = 0.208, SEE = 2.194
0.156 0.029 0.018 0.126
<.001*** .483 .528 .813
Temporal summation NWR threshold Group (patients–control) 0.759 BDI 0.018 STAI-State 0.007 CSQ catastrophizing 0.029 R2 = 0.110, SEE = 2.271
0.166 0.030 0.019 0.130
<.001*** .550 .722 .825
Reflex receptive field area Group (patients–control) BDI STAI-State CSQ catastrophizing R2 = 0.049, SEE = 0.175
Coefficient
NWR, nociceptive withdrawal reflex; BDI, Beck Depression Inventory; STAI, StateTrait Anxiety Inventory; CSQ Catastrophizing, Catastrophizing Scale of the Coping Strategies Questionnaire; R2, proportion of the variation explained by the model; SE, standard error; SEE, standard error of estimates. * P < .05. *** P < .001.
some cases also to distinguish between acute pain patients and chronic pain patients. It has to be noted that these differences between acute and chronic pain patients were significant for some but not all pain tests, most likely because these differences were too small to be detected with the sample size presented here,
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which was calculated on the basis of expected RRF area differences between chronic pain patients and healthy volunteers [29]. To date, there are no models to explain the transition from acute to chronic states, or, in a related topic, from localized pain (possibly caused by tissue challenges) to widespread pain conditions. One hypothesis suggests that tissue injury (and the related nociception from deep tissue) causes a progressive sensitization of the nociceptive system at various segmental spinal levels and higher brain centers, leading to widespread pain hypersensitivity when a larger parts of the nociceptive neuraxis is sensitized [19]. In any case, the progressive decrease in thresholds found in this study could potentially have great prognostic value; it could be used to identify patients at risk of developing chronic pain conditions and to develop strategies for early intervention that aim to correct such alterations. 4.3. Limitations and future work Direct assessment of central pain processing in humans is not possible; for example, a proper neuronal receptive field mapping would require in vivo spinal recordings. Consequently, all assessment methods currently available are indirect measures of nociception. From these, the NWR measures stand out from traditional psychophysical assessments because they do not involve a conscious decision from the researcher/physician or the subject/patient. However, it is subjected to supraspinal modulation, and thus external factors (eg, involving affective and cognitive processes) can affect the NWR characteristics [1,33,36]; thus, these factors have to be carefully controlled for in order to provide reliable outcomes. The RRF assessment requires particular care because it is based on the assumption of providing equal pain input to the spinal cord, so it relies on the assessment of subjective pain thresholds [1]. Thus, new methodologies need to be developed in order to overcome this limitation. Finally, it has to be noted that while most studies focus on differences between groups of patients and groups of controls subjects, the next step in the translation from experimental research to clinical practice requires the development of tools to detect abnormalities in individual patients. 4.4. Conclusions The present investigation provides evidence that acute and chronic musculoskeletal pain conditions are characterized by an
Fig. 3. Grand mean RRF obtained by averaging the NWR responses from all subjects in each group (depicting the RRF of an average subject for each group). White dots indicate the stimulation sites; black line, contour of the RRF area; and colors, reflex magnitude. RRF, reflex receptive field; CNP, chronic neck pain; CLBP, chronic low back pain; ALBP, acute low back pain; CTRL, control.
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enlargement of the RRF. These results contribute to a better understanding of the central mechanisms underlying these pain conditions. Specifically, the most likely mechanism behind this phenomenon is widespread spinal hyperexcitability, which is also reflected in increased response magnitudes, lower thresholds, and enhanced temporal summation. Furthermore, these findings support the use of RRF and the NWR as objective biomarkers for pain hypersensitivity in clinical and experimental pain research. Conflict of interest statement The authors report no conflict of interest. Acknowledgments This research was supported by the Danish Research Council for Technology and Production Sciences (FTP), the Swiss National Science Foundation (Grant 3247BO_122358/1), and the Scientific Funds of the University Department of Anesthesiology and Pain Therapy of the University of Bern. References [1] Andersen OK. Studies of the organization of the human nociceptive withdrawal reflex. Focus on sensory convergence and stimulation site dependency. Acta Physiol 2007;189:1–35. [2] Andersen OK, Sonnenborg FA, Arendt-Nielsen L. Modular organization of human leg withdrawal reflexes elicited by electrical stimulation of the foot sole. Muscle Nerve 1999;22:1520–30. [3] Arendt-Nielsen L, Brennum J, Sindrup S, Bak P. Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system. Eur J Appl Physiol Occup Physiol 1994;68:266–73. [4] Arendt-Nielsen L, Graven-Nielsen T. Muscle pain: sensory implications and interaction with motor control. Clin J Pain 2008;24:291–8. [5] Banic B, Petersen-Felix S, Andersen OK, Radanov BP, Villiger PM, ArendtNielsen L, Curatolo M. Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia. PAINÒ 2004;107:7–15. [6] Manresa JA, Jensen MB, Andersen OK. Introducing the reflex probability maps in the quantification of nociceptive withdrawal reflex receptive fields in humans. J Electromyogr Kinesiology 2011;21:67–76. [7] Biurrun Manresa JA, Neziri AY, Curatolo M, Arendt-Nielsen L, Andersen OK. Test–retest reliability of the nociceptive withdrawal reflex and electrical pain thresholds after single and repeated stimulation in patients with chronic low back pain. Eur J Appl Physiol 2011;111:83–92. [8] Bouhassira D, Danziger N, Atta N, Guirimand F. Comparison of the pain suppressive effects of clinical and experimental painful conditioning stimuli. Brain 2003;126:1068–78. [9] Bouhassira D, Sabaté J, Coffin B, Le Bars D, Willer J, Jian R. Effects of rectal distensions on nociceptive flexion reflexes in humans. Am J Physiol Gastrointest Liver Physiol 1998;275:G410–7. [10] Carragee EJ, Tanner CM, Khurana S, Hayward C, Welsh J, Date E, Truong T, Rossi M, Hagle C. The rates of false-positive lumbar discography in select patients without low back symptoms. Spine 2000;25:1373–81. [11] Cook AJ, Woolf CJ, Wall PD, McMahon SB. Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input. Nature 1987;325:151–3. [12] Curatolo M. Diagnosis of altered central pain processing. Spine 2011;36:S200–4. [13] Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Giani C, Zbinden AM, Radanov BP. Central hypersensitivity in chronic pain after whiplash injury. Clin J Pain 2001;17:306–15. [14] Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P, Dayer P, Vischer TL. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum 2003;48:1420–9. [15] Dubner R, Basbaum AI. Spinal dorsal horn plasticity following tissue or nerve injury. In: Wall PD, Melzack R, editors. Textbook of pain. Edinburgh: Churchill Livingstone; 1994. p. 225–41. [16] Emery CF, Keefe FJ, France CR, Affleck G, Waters S, Fondow MDM, McKee DC, France JL, Hackshaw KV, Caldwell DS, Stainbrook D. Effects of a brief coping skills training intervention on nociceptive flexion reflex threshold in patients having osteoarthritic knee pain: a preliminary laboratory study of sex differences. J Pain Symptom Manage 2006;31:262–9. [17] French DJ, France CR, France JL, Arnott LF. The influence of acute anxiety on assessment of nociceptive flexion reflex thresholds in healthy young adults. PAINÒ 2005;114:358–63. [18] Goffaux P, Redmond WJ, Rainville P, Marchand S. Descending analgesia—when the spine echoes what the brain expects. PAINÒ 2007;130:137–43. [19] Graven-Nielsen T, Arendt-Nielsen L. Assessment of mechanisms in localized and widespread musculoskeletal pain. Nat Rev Rheumatol 2010;6:599–606.
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[25] Neziri AY, Andersen OK, Petersen-Felix S, Radanov B, Dickenson AH, Scaramozzino P, Arendt-Nielsen L, Curatolo M. The nociceptive withdrawal reflex: normative values of thresholds and reflex receptive fields. Eur J Pain 2010;14:134–41. [26] Neziri AY, Curatolo M, Bergadano A, Petersen-Felix S, Dickenson A, ArendtNielsen L, et al. New method for quantification and statistical analysis of nociceptive reflex receptive fields in humans. J Neurosci Methods 2009;178:24–30. [27] Neziri AY, Curatolo M, Limacher A, Nüesch E, Radanov B, Andersen OK, ArendtNielsen L, Jüni P. Ranking of parameters of pain hypersensitivity according to their discriminative ability in chronic low back pain. PAINÒ 2012;153:2083–91. [28] Neziri AY, Curatolo M, Nüesch E, Scaramozzino P, Andersen OK, ArendtNielsen L, Jüni P. Factor analysis of responses to thermal, electrical, and mechanical painful stimuli supports the importance of multi-modal pain assessment. PAINÒ 2011;152:1146–55. [29] Neziri AY, Haesler S, Petersen-Felix S, Müller M, Arendt-Nielsen L, Manresa JB, Andersen OK, Curatolo M. Generalized expansion of nociceptive reflex receptive fields in chronic pain patients. PAINÒ 2010;151:798–805. [30] Neziri AY, Manresa JB, Jüni P, Arendt-Nielsen L, Andersen OK, Curatolo M. Expansion of nociceptive reflex receptive fields in patients with low back and neck pain. Eur J Pain Suppl 2011;5:109–10. [31] Price DD, Staud R, Robinson ME, Mauderli AP, Cannon R, Vierck CJ. Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. PAINÒ 2002;99:49–59. [32] Rhudy JL, France CR. Reliability and validity of a brief method to assess nociceptive flexion reflex (NFR) threshold. J Pain 2011;12:782–91. [33] Rhudy JL, Martin SL, Terry EL, Delventura JL, Kerr KL, Palit S. Using multilevel growth curve modeling to examine emotional modulation of temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR). PAINÒ 2012;153:2274–82. [34] Rolke R, Baron R, Maier C, Tölle TR, Treede R-D, Beyer A, Binder A, Birbaumer N, Birklein F, Bötefür IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihöfner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. PAINÒ 2006;123:231–43. [35] Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ. Interleukin-1b-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001;410:471–5. [36] Sandrini G, Serrao M, Rossi P, Romaniello A, Cruccu G, Willer JC. The lower limb flexion reflex in humans. Prog Neurobiol 2005;77:353–95. [37] Serrao M, Rossi P, Sandrini G, Parisi L, Amabile GA, Nappi G, Pierelli F. Effects of diffuse noxious inhibitory controls on temporal summation of the RIII reflex in humans. PAINÒ 2004;112:353–60. 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PAIN 154 (2013) 1318–1324
www.elsevier.com/locate/pain
Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain José A. Biurrun Manresa a,⇑,1, Alban Y. Neziri b,c,1, Michele Curatolo b, Lars Arendt-Nielsen a, Ole K. Andersen a a b c
Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 7, 9220 Aalborg Øst, Denmark University Department of Anesthesiology and Pain Therapy, University Hospital of Bern, Inselspital, Freiburgstrasse, 3010 Bern, Switzerland Department of Obstetrics and Gynaecology, Cantonal Hospital of St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
a r t i c l e
i n f o
Article history: Received 13 November 2012 Received in revised form 12 March 2013 Accepted 3 April 2013
Keywords: Central hyperexcitability Low back pain Neck pain Nociceptive withdrawal reflex Pain hypersensitivity Reflex receptive field
a b s t r a c t Pain hypersensitivity has been consistently detected in chronic pain conditions, but the underlying mechanisms are difficult to investigate in humans and thus poorly understood. Patients with endometriosis pain display enlarged reflex receptive fields (RRF), providing a new perspective in the identification of possible mechanisms behind hypersensitivity states in humans. The primary hypothesis of this study was that RRF are enlarged in patients with musculoskeletal pain. Secondary study end points were subjective pain thresholds and nociceptive withdrawal reflex (NWR) thresholds after single and repeated (temporal summation) electrical stimulation. Forty chronic neck pain patients, 40 chronic low back pain patients, and 24 acute low back pain patients were tested. Electrical stimuli were applied to 10 sites on the sole of the foot to quantify the RRF, defined as the area of the foot from where a reflex was evoked. For the secondary end points, electrical stimuli were applied to the cutaneous innervation area of the sural nerve. All patient groups presented enlarged RRF areas compared to pain-free volunteers (P < .001). Moreover, they also displayed lower NWR and pain thresholds to single and repeated electrical stimulation (P < .001). These results demonstrate that musculoskeletal pain conditions are characterized by enlarged RRF, lowered NWR and pain thresholds, and facilitated temporal summation, most likely caused by widespread spinal hyperexcitability. This study contributes to a better understanding of the mechanisms underlying these pain conditions, and it supports the use of the RRF and NWR as objective biomarkers for pain hypersensitivity in clinical and experimental pain research. Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Pain hypersensitivity is an expression of neuronal plasticity that causes an amplification of the pain sensation, which depends on specific patterns of activation, modulation, or modification of the nociceptive input [46]. It is usually characterized as a state of hyperexcitability of the central nervous system and changes in endogenous pain modulation, resulting in painful perceptions to normally innocuous stimuli (allodynia) or to exaggerated responses to painful stimuli (hyperalgesia). The mechanisms also include facilitated temporal summation and enlargement of the referred pain areas. These alterations are commonly present in chronic musculoskeletal conditions [20], and they are likely relevant from a clinical perspective, as they influence the magnitude ⇑ Corresponding author. Tel.: +45 9940 8715; fax: +45 9815 4008. 1
E-mail address: [email protected] (J.A. Biurrun Manresa). These authors contributed equally to this work.
of pain and disability [12]. Although pain hypersensitivity has been consistently detected in chronic pain, the underlying mechanisms are difficult to investigate in humans and therefore poorly understood. The assessment of the underlying central mechanisms behind pain hypersensitivity in humans is a challenging task because direct neural recording is not possible. Instead, a series of psychophysical quantitative sensory tests are usually performed in order to assess a characteristic constellation of sensory signs and symptoms that can be associated with hypersensitivity [34,46]. The rationale behind these tests is that pain hypersensitivity detected after stimulation of healthy tissue has to be a consequence of alterations in central processing [12]. The use of quantitative sensory tests has brought great advancement in the field of pain research; however, they are bounded by inherent limitations, such as their subjective nature, allowing them to be biased, modulated, or influenced by factors not necessarily influencing the central nociceptive processing [43].
0304-3959/$36.00 Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.pain.2013.04.013
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Electrophysiological tests can also be used to assess nociceptive hyperexcitability. In particular, tests based on the nociceptive withdrawal reflex (NWR) and reflex receptive fields (RRF) display some advantages over psychophysical assessments. In the first place, they are objective, in the sense that the outcome of the test does not directly rely on conscious decisions from the researcher/ physician or the subject/patient under controlled experimental conditions. They have demonstrated high reliability when performed in healthy volunteers [23,32] as well as in patients with painful conditions [7]. More importantly, they also provide some insight into the location and mechanisms behind the alterations, revealing that at least part of the hypersensitivity is the result of spinal hyperexcitability [14,41]. In relation to this, a recent investigation revealed that patients with endometriosis pain display enlarged RRF [29], thus opening a new perspective in the identification of possible mechanisms underlying hypersensitivity states in humans. The primary aim of the present study was to test the hypothesis that RRF are enlarged in patients with acute and chronic musculoskeletal pain conditions compared to healthy volunteers. Additionally, NWR and pain thresholds after single and repeated electrical stimulation of the sural nerve were analyzed in order to test subjective pain sensitivity, facilitated temporal summation, and spinal excitability. The results were expected to provide insights into the mechanisms underlying chronic musculoskeletal pain and to offer a perspective to identify potential biomarkers for the objective assessment of central hyperexcitability in humans.
2. Materials and methods 2.1. Participants 2.1.1. Patients Patients were recruited at the Department of Anaesthesiology and Pain Therapy of the University Hospital of Bern, Inselspital. Forty patients with chronic neck pain, 40 patients with chronic low back pain, and 24 patients with acute low back pain participated in the study. The patients with chronic low back pain were part of a case-control study that was recently published [27]. Inclusion criteria for chronic pain patients were daily pain of at least 6 months’ duration and pain at the time of testing with an intensity of at least 3 on a 10-cm visual analog scale, with 0 indicating no pain and 10 the worst pain imaginable. Inclusion criteria for acute pain patients were daily pain for no longer than 4 weeks, no history of chronic low back pain, and pain at the time of testing with an intensity of at least 3 on a 10-cm visual analog scale, with 0 indicating no pain and 10 the worst pain imaginable. Exclusion criteria were radicular pain (as defined by leg pain associated with a magnetic resonance imaging finding of herniated disc or foraminal stenosis with contact to a nerve root), peripheral or central neurological disorders, diabetes mellitus, insufficient knowledge of the German language, pregnancy (as excluded by a pregnancy test), breast-feeding, intake of oral contraceptives or hormones, intake of opioids and antidepressants during the previous 2 weeks, and intake of other analgesics during the 48 h before testing. All subjects provided written informed consent before participating. The study protocol was approved by the local ethics committee of the Canton of Bern, and the study was performed in accordance with the Declaration of Helsinki.
2.1.2. Pain-free subjects The control group consisted of 300 pain-free subjects who had been recently analyzed to determine the reference values of the reflex parameters in the pain-free population [25]. Exclusion criteria
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were the same as for the patient group, plus the following: any pain at the time of testing or history of chronic pain syndrome of any nature. 2.2. Descriptive variables To provide comprehensive information about the patient population, several descriptive variables were recorded, including gender, age, height, weight, and body mass index, pain intensity at the time of testing, and maximum pain intensity ever experienced. Volunteers were also asked to complete the following questionnaires: Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), and Catastrophizing Scale of the Coping Strategies Questionnaire (CSQ). A thorough description of the questionnaires is provided by Neziri et al. [29]. 2.3. Electrophysiological and psychophysical pain tests The main end point according to the study hypothesis was the assessment of RRF. Secondary end points were subjective pain thresholds and parameters of spinal cord nociceptive excitability, namely NWR thresholds to single and repeated electrical stimulation. All the experiments were performed by the same investigator (AN). During the testing session, the volunteers were lying in a bed in a quiet room. A leg rest was placed under the knee to obtain a 10° flexion. Each subject underwent a training session for all tests in order to get familiar with the stimulation procedures before starting the data collection. Tests for RRF, single electrical stimulation, and repeated electrical stimulation were performed in a randomized order. All the tests were applied to the same body side within each subject, with the side being selected randomly by the investigator in a ratio of 1:1. 2.3.1. RRF assessment [26] have previously described a detailed procedure to assess the RRF. In short, 10 surface electrodes (15 15 mm, type 700, Ambu A/S, Denmark) were mounted on the sole of the foot, and a common anode (50 90 mm electrode, type Synapse, Ambu A/S, Denmark) was placed on the dorsum of the foot. Each stimulus consisted of a constant current pulse train of 5 individual 1-ms pulses delivered at 200 Hz (Stimulator Noxitest IES 230, Aalborg University, Denmark), felt as a single stimulus. The current intensity was increased from 1 mA in steps of 0.5 mA as the pain sensation was evoked (pain threshold) for each of the 10 stimulation sites. To avoid the subjects’ gradual adaptation to the stimulus while determining the pain thresholds at the different sites, the identified pain threshold at the arch of the foot was repeatedly presented to the volunteer for reference. After all pain thresholds were determined, a stimulus with an intensity equal to that 1.5 times higher than the individual pain threshold was delivered 4 times to each individual site, for a total of 40 stimulations. A computercontrolled electrical relay delivered the stimulus to 1 of the 10 electrodes in a randomized sequence at random time intervals (between 8 and 12 s), so that the subject was not aware of when the stimulus was applied. The NWR was measured by surface electromyographic (EMG) electrodes (type 720, Ambu A/S, Denmark) over the belly of the tibialis anterior muscle (interelectrode distance of 2 cm) because the expected biomechanical response to stimulation of the sole of the foot is primarily ankle dorsiflexion [2]. The EMG signals were amplified (up to 50,000 times), filtered (5–500 Hz, second order), sampled (2000 Hz), displayed on the computer screen, and stored on a computer disk. The EMG signals were recorded from 200 ms before stimulation until 1000 ms after stimulation onset. EMG reflex responses were quantified using root– mean–square (RMS) amplitude in the 60–180-ms poststimulation
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interval. RRF sensitivity maps were derived by 2-dimensional interpolation of the RMS amplitudes. RRF sensitivity areas were calculated as the fraction of the sole of the foot delimited by a threshold set by the peak RMS amplitude minus 2 times the standard deviation of the remaining RMS amplitudes. 2.3.2. Thresholds to single electrical stimulation Electrical stimulation was performed through surface electrodes placed caudal to the lateral malleolus, at the innervation area of the sural nerve [5]. The same train of five 1-ms square wave pulses delivered at 200 Hz was used. EMG reflex responses to electrical stimulation were recorded from the belly of the biceps femoris and the rectus femoris muscles by surface electrodes (type 720, Ambu A/S, Denmark) because the expected biomechanical response to stimulation of the sural nerve is primarily knee–hip flexion [2,5]. The current intensity was increased from 1 mA in steps of 0.5 mA until: (1) a reflex with an amplitude exceeding 20 lV for at least 10 ms in the 60–180-ms poststimulation interval was detected (single stimulus NWR threshold); and (2) a pain sensation was evoked (single stimulus pain threshold). These procedures were repeated 3 times, and the median value was used as the respective thresholds. 2.3.3. Thresholds to repeated electrical stimulation (temporal summation) The stimulus burst used for single stimulus was repeated 5 times at a frequency of 2 Hz and at constant stimulus intensity [3]. EMG recordings were similar as for single stimulation. The current intensity of the 5 constant stimuli was increased from 1 mA in steps of 0.5 mA until: (1) an increase in the amplitude of the last 1– 3 reflexes above a fixed limit of 20 lV for at least 10 ms in the 70– 150-ms poststimulation interval was observed (temporal summation NWR threshold); and (2) the subjects felt pain during the last 1–3 of the 5 electrical bursts (temporal summation pain threshold). These procedures were repeated 3 times, and the median value was used as the respective thresholds. 2.4. Data analysis 2.4.1. Sample size considerations In agreement with previous studies [29], it was established that a significant difference of 0.144 in RRF area among groups would be detected by a sample size of 17 subjects per group. To minimize the likelihood of insufficient power due to unexpected higher variability, it was decided to study at least 24 patients per group. Therefore, consecutive patients were recruited until all the groups reached the minimum size of 24 patients. 2.4.2. Statistical analyses Descriptive variables (demographic, psychological, and health related) and quantitative variables derived from electrophysiological and psychophysical pain tests (RRF areas, NWR, and pain thresholds) between groups were compared by the Kruskall-Wallis test (for nonnormally distributed data). Post hoc pairwise comparisons were performed by the Wilcoxon test. P values of <.05 were considered significant. In order to study the independent contribution of psychological factors, multiple linear regression analyses were conducted on each test, ie, RRF area, pain, and reflex thresholds to single and repeated electrical stimulation. In all 5 regressions, the following independent (explanatory) variables were analyzed: group (patients or controls), BDI, STAI-State and CSQ catastrophizing (STAI-Trait was excluded as a result of collinearity with STAI-State). All values are presented as median (25% quartile– 75% quartile).
3. Results 3.1. Descriptive variables The statistical analysis of descriptive variables from the different groups is presented in Table 1. Among the demographic variables, height and body mass index presented a statistically significant difference among groups (Kruskall-Wallis, P = .007 and P = .012, respectively), although it does not seem to bear any relevance in relation to the quantitative variables derived from the electrophysiological and psychophysical tests. On the other hand, patients presented statistically significant higher scores in all psychological variables (BDI, STAI-State, STAI-Trait, and CSQ catastrophizing) compared to controls (Wilcoxon, all P values <.001), with the exception of CSQ catastrophizing scores between acute low back pain patients and controls (Wilcoxon, P = .879). Moreover, there were also differences between acute and chronic pain patients. BDI, STAI-Trait, and CSQ catastrophizing scores were significantly lower in acute low back pain patients compared to chronic low back pain and chronic neck pain patients (Wilcoxon, P values ranging from <.001 to .005), whereas STAI-State scores were significantly lower in acute low back pain patients than in chronic neck pain patients (Wilcoxon, P = .047), but they were not significantly different from chronic low back pain patients scores (Wilcoxon, P = .129). 3.2. Electrophysiological and psychophysical pain tests The statistical analysis of quantitative variables derived from electrophysiological and psychophysical pain tests (RRF area, NWR and pain thresholds to single and repeated stimulation) is presented in Table 2 and illustrated in Figs. 1 and 2. All quantitative variables presented statistically significant differences between groups (Kruskall-Wallis, P < .001 for all tests). Post hoc pairwise comparisons revealed statistically significant differences between patients and controls; specifically, patients presented larger RRF areas (Wilcoxon, P values ranging from .001 to .047), lower single stimulation pain thresholds (Wilcoxon, all P values <.001), lower single stimulation NWR thresholds (Wilcoxon, all P values <.001), lower temporal summation pain thresholds (Wilcoxon, all P values <.001), and lower temporal summation NWR thresholds (Wilcoxon, P values ranging from <.001 to .013). Furthermore, chronic neck pain patients displayed lower single stimulation NWR thresholds (Wilcoxon, P = .033) and lower temporal summation pain thresholds (Wilcoxon, P = .017) compared to acute low back pain patients. 3.3. Multiple linear regression The results of the multiple linear regression analysis demonstrated that the predictors selected for accounted for 5% to 31% of the variance of the quantitative variables derived from electrophysiological and psychophysical pain tests (Table 3). In all cases, group was a statistically significant predictor (P < .001). Moreover, none of the psychological factors was significantly related to these variables, with the exception of STAI-State for single stimulation pain threshold (P = .016).
4. Discussion The main results of this study demonstrated that all patient groups with musculoskeletal pain conditions presented enlarged RRF areas compared to pain-free volunteers. Moreover, all patients displayed lower NWR and pain thresholds to single and repeated electrical stimulation compared to healthy subjects. Additionally,
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J.A. Biurrun Manresa et al. / PAIN 154 (2013) 1318–1324 Table 1 Demographic and psychological variables of the study population.a Characteristic
Chronic neck pain (n = 40)
Chronic low back pain (n = 40)
Acute low back pain (n = 23)
Controls (n = 300)
P
Age, y Height, cm Weight, kg BMI, kg/m2 Posttraumatic onset of pain Pain duration Current pain intensity rating, VAS Highest pain intensity rating, VAS BDI, score 0–63 STAI-State, score 20–80 STAI-Trait, score 20–80 CSQ catastrophizing, score 0–6
49 (42–62) 168 (163–175) 70 (64–80) 24.8 (22.3–27.6) 20 (50%) 51.0 (24.0–66.8) 5.4 (4.6–6.7) 9.0 (8.0–9.6) 10 (7–17) 58 (48–69) 56 (48–69) 3.0 (2.0–4.2)
50 (40–60) 172 (164–178) 74 (68–85) 25.7 (23.2–27.7) 0 (0%) 48.0 (13.8–111.0) 4.6 (4.2–5.8) 9.0 (8.3–10.0) 11 (7–17) 54 (46–65) 57 (48–69) 3.2 (2.2–4.2)
39 (30–54) 176 (168–185) 72 (68–84) 23.6 (21.7–25.6) 0 (%) 1.0 (1.0–2.5) 5.0 (4.0–6.0) 7.0 (6.0–8.0) 4 (2–8) 50 (46–55) 46 (41–54) 2.0 (1.2–2.7)
49 (34–65) 174 (168–180) 73 (63–85) 23.6 (21.9–26.3) NA NA NA NA 1 (0–4) 44 (41–47) 41 (38–46) 1.8 (1.3–2.6)
.071 .007** .587 .012* NA NA NA NA <.001*** <.001*** <.001*** <.001***
VAS, visual analog scale; BMI, body mass index; BDI, Beck Depression Inventory; STAI, State-Trait Anxiety Inventory; CSQ, Coping Strategies Questionnaire; NA, not applicable. a Numerical variables are presented as median (25% quartile–75% quartile). Categorical variables are presented as number of subjects in each group (percentage in relation to the group). Pain duration is expressed in months for chronic pain patients and in weeks for acute pain patients. * P < .05. ** P < .01. *** P < .001.
Table 2 Reflex receptive field areas and NWR and pain thresholds after single and repeated electrical stimulation.a Characteristic
Chronic neck pain patients (n = 40)
Chronic low back pain patients (n = 40)
Acute low back pain patients (n = 24)
Controls (n = 300)
P
Reflex receptive field area, fraction of the foot sole Single stimulation pain threshold, mA Single stimulation NWR threshold, mA Temporal summation pain threshold, mA Temporal summation NWR threshold, mA
0.40 (0.29–0.48) 6.2 (5.3–8.0) 9.3 (7.3–12.6) 5.0 (4.0–6.5) 5.6 (5.0–8.0)
0.39 (0.26–0.55) 6.8 (5.3–8.9) 10.3 (7.3–14.7) 6.0 (4.0–7.0) 7.0 (5.1–8.7)
0.46 (0.32–0.56) 8.0 (6.0–10.0) 12.0 (10.0–14.3) 7.0 (5.7–8.0) 7.0 (5.7–8.7)
0.30 (0.18–0.44) 11.0 (9.0–12.0) 16.0 (14.0–18.0) 8.3 (7.0–9.7) 8.3 (7.0–9.7)
<.001*** <.001*** <.001*** <.001*** <.001***
NWR, nociceptive withdrawal reflex. a Numerical variables are presented as median (25% quartile–75% quartile). *** P < .001.
chronic neck pain patients displayed lower single stimulation NWR thresholds and lower temporal summation pain thresholds compared to acute low back pain patients. These findings suggest that plasticity changes may lead to expansion of neuronal receptive fields or increased responsiveness of spinal neurons and facilitated temporal summation, which are likely important determinants of pain amplification. Accordingly, these assessment methods can be used as objective biomarkers of alterations in nociceptive processes in human musculoskeletal pain. 4.1. Assessment of pain hypersensitivity Pain hypersensitivity can be assessed by several different experimental tests: verbal reports, pain questionnaires, light touch, and vibration, as well as detection, first pain, and tolerance thresholds to pressure, electrical, heat, and cold stimuli [13,21,24,31,38–40]. In a recent study that ranked these tests according to their discriminative ability in chronic low back pain patients, pressure and electrical pain modalities demonstrated the most promising results [27]. However, the perception of pain is a complex multisensory experience, and different modalities assessed simultaneously are likely to provide a more complete representation of the nociception and pain experience [28]. In any case, most of the aforementioned methods used to assess pain hypersensitivity in humans rely on volunteer reports after sensory stimulation, which are subjective in nature. As such, they can be voluntarily and/or involuntarily affected by a number of factors, including the psychological distress associated with chronic pain conditions [10,22]. Nowadays, there is increasing evidence that objective methods, such as those based on the NWR and the RRF, can detect hyperexcitability in the nociceptive pathways
without the setbacks usually associated with subjective assessments. Indeed, measures derived from the NWR and the RRF are reliable [7,23,32] and stable against habituation [6] or other biasing factors, including psychological factors such as anxiety, depression, mental health, or pain catastrophizing [30]. The results of this study also demonstrated marked differences between patients and pain-free subjects; specifically, all patient groups displayed lower NWR and pain thresholds and larger RRF areas (Table 2). Several differences were also found in the psychological descriptors between these groups (Table 1), although in most cases these differences were not correlated with the outcome variables from the electrophysiological and psychophysical tests (Table 3). A single exception was found for single stimulation pain thresholds, which were correlated to anxiety state. This is in line with previous studies investigating the effect of anxiety on pain tests, in which subjective pain reports (such as electrical pain thresholds), but not objective measures (NWR thresholds and RRF areas), may be influenced by anxiety under standard testing conditions [17,30,44]. In general terms, none of the psychological factors are good predictors for changes in the quantification variables (RRF areas, NWR and pain thresholds), so this is an indication that the differences found in the pain tests are not likely related to disparities in psychological profiles among groups. 4.2. Mechanisms of pain hypersensitivity Pain hypersensitivity is characterized by dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, enhanced temporal summation, and enlargement of referred pain areas [20,45]. Experimental and clinical studies in diverse cohorts of patients (eg, whiplash, fibromyalgia, osteoarthritis,
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Fig. 1. Pain (left) and NWR (right) thresholds for single (top) and repeated (bottom) electrical stimulation. Data are presented as median, 10th, 25th, 75th, and 90th percentiles. Black dots represent the values that lie outside the 10th and 90th percentiles. NWR, nociceptive withdrawal reflex; CNP, chronic neck pain; CLBP, chronic low back pain; ALBP, acute low back pain; CTRL, control. ⁄P < .05; ⁄⁄⁄P < .001.
Fig. 2. Reflex receptive field areas, expressed as a fraction of the sole of the foot from which a reflex in the tibialis anterior muscle was elicited. Data are presented as median, 10th, 25th, 75th, and 90th percentiles. Black dots represent the values that lie outside the 10th and 90th percentiles. CNP, chronic neck pain; CLBP, chronic low back pain; ALBP, acute low back pain; CTRL, control. ⁄P < .05, ⁄⁄P < .01.
musculoskeletal disorders, headache, and neuropathic, visceral, and postsurgical pain) have demonstrated common features that are likely to reflect alterations in central pain processing [12,45]. It has been previously demonstrated that chronic pain due to endometriosis is associated with larger RRF areas compared to pain-free subjects [29]. Clearly, observations in a specific visceral pain condition are not necessarily applicable to other chronic pain conditions.
The main finding of the present study was that RRF areas were enlarged in patients with musculoskeletal pain compared to painfree volunteers. (The grand mean RRF areas for each group can be seen in Fig. 3.) The enlargement of RRF would indicate that spinal hyperexcitability could be a consequence of increased number of responsive spinal neurons or an expansion of the receptive fields of spinal neurons as a result of increased synaptic sensitivity [11,15]. In both cases, the RRF expansion was detected in areas distant from the site of expected tissue damage, indicating widespread spinal hyperexcitability [4,39]. Animal experiments indicate that humoral factors and/or alterations in the descending modulatory system may be at least partially responsible for this behavior [35,42,47], although the current evidence in humans does not allow to make a precise description of the mechanisms behind these phenomena [8,9,16,18,37]. Both acute and chronic pain patients displayed lower NWR thresholds after a single electrical stimulation compared to painfree volunteers. Moreover, temporal summation mechanisms were also altered in patients because NWR thresholds were also significantly lower after repeated electrical stimulation. These results are consistent with previous studies including patients with different clinical conditions, such as whiplash, fibromyalgia, and endometriosis [5,14,29]. Together, these results can be interpreted as electrophysiological evidence for central spinal hyperexcitability in these patient groups. Interestingly, the assessment of NWR and pain thresholds resulted in a graded outcome, in which it was possible to discriminate between pain-free volunteers and acute pain patients, but in
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J.A. Biurrun Manresa et al. / PAIN 154 (2013) 1318–1324 Table 3 Multiple regression analysis for quantitative variables derived from electrophysiological and psychophysical pain tests. Characteristic
SE
P
0.054 0.002 9.7e 6 0.005
0.013 0.002 0.001 0.012
<.001*** .365 .994 .574
Single stimulation pain threshold Group (control) BDI STAI-State CSQ catastrophizing R2 = 0.309, SEE = 2.471
1.504 0.003 0.049 0.078
0.180 0.032 0.020 0.141
<.001*** .920 .016* .584
Single stimulation NWR threshold Group (patients–control) BDI STAI-State CSQ catastrophizing R2 = 0.294, SEE = 3.732
2.315 0.001 0.046 0.073
0.273 0.049 0.030 0.215
<.001*** .778 .127 .733
Temporal summation pain threshold Group (patients–control) 1.085 BDI 0.020 STAI-State 0.011 CSQ catastrophizing 0.030 R2 = 0.208, SEE = 2.194
0.156 0.029 0.018 0.126
<.001*** .483 .528 .813
Temporal summation NWR threshold Group (patients–control) 0.759 BDI 0.018 STAI-State 0.007 CSQ catastrophizing 0.029 R2 = 0.110, SEE = 2.271
0.166 0.030 0.019 0.130
<.001*** .550 .722 .825
Reflex receptive field area Group (patients–control) BDI STAI-State CSQ catastrophizing R2 = 0.049, SEE = 0.175
Coefficient
NWR, nociceptive withdrawal reflex; BDI, Beck Depression Inventory; STAI, StateTrait Anxiety Inventory; CSQ Catastrophizing, Catastrophizing Scale of the Coping Strategies Questionnaire; R2, proportion of the variation explained by the model; SE, standard error; SEE, standard error of estimates. * P < .05. *** P < .001.
some cases also to distinguish between acute pain patients and chronic pain patients. It has to be noted that these differences between acute and chronic pain patients were significant for some but not all pain tests, most likely because these differences were too small to be detected with the sample size presented here,
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which was calculated on the basis of expected RRF area differences between chronic pain patients and healthy volunteers [29]. To date, there are no models to explain the transition from acute to chronic states, or, in a related topic, from localized pain (possibly caused by tissue challenges) to widespread pain conditions. One hypothesis suggests that tissue injury (and the related nociception from deep tissue) causes a progressive sensitization of the nociceptive system at various segmental spinal levels and higher brain centers, leading to widespread pain hypersensitivity when a larger parts of the nociceptive neuraxis is sensitized [19]. In any case, the progressive decrease in thresholds found in this study could potentially have great prognostic value; it could be used to identify patients at risk of developing chronic pain conditions and to develop strategies for early intervention that aim to correct such alterations. 4.3. Limitations and future work Direct assessment of central pain processing in humans is not possible; for example, a proper neuronal receptive field mapping would require in vivo spinal recordings. Consequently, all assessment methods currently available are indirect measures of nociception. From these, the NWR measures stand out from traditional psychophysical assessments because they do not involve a conscious decision from the researcher/physician or the subject/patient. However, it is subjected to supraspinal modulation, and thus external factors (eg, involving affective and cognitive processes) can affect the NWR characteristics [1,33,36]; thus, these factors have to be carefully controlled for in order to provide reliable outcomes. The RRF assessment requires particular care because it is based on the assumption of providing equal pain input to the spinal cord, so it relies on the assessment of subjective pain thresholds [1]. Thus, new methodologies need to be developed in order to overcome this limitation. Finally, it has to be noted that while most studies focus on differences between groups of patients and groups of controls subjects, the next step in the translation from experimental research to clinical practice requires the development of tools to detect abnormalities in individual patients. 4.4. Conclusions The present investigation provides evidence that acute and chronic musculoskeletal pain conditions are characterized by an
Fig. 3. Grand mean RRF obtained by averaging the NWR responses from all subjects in each group (depicting the RRF of an average subject for each group). White dots indicate the stimulation sites; black line, contour of the RRF area; and colors, reflex magnitude. RRF, reflex receptive field; CNP, chronic neck pain; CLBP, chronic low back pain; ALBP, acute low back pain; CTRL, control.
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