ORIGINAL ARTICLE
Dynamic Changes in Nociception and Pain Perception After Spinal Cord Stimulation in Chronic Neuropathic Pain Patients Jose´ A. Biurrun Manresa, PhD,* Jan So¨rensen, MD, PhD,wz Ole K. Andersen, PhD, dr scient,* Lars Arendt-Nielsen, PhD, dr scient med,* and Bjo¨rn Gerdle, MD, PhDwz
Objectives: Patients with an implanted spinal cord stimulation (SCS) system for pain management present an opportunity to study dynamic changes in the pain system in a situation where patients are not stimulated (ie, experiencing severe pain) compared with a situation in which patients have just been stimulated (ie, pain free or greatly reduced pain). The aims of this study were (1) to determine if there are differences in nociceptive withdrawal reflex thresholds (NWR-T) and electrical pain thresholds (EP-T) before and after SCS; and (2) to establish if these differences are related to psychological factors associated with chronic pain. Methods: Seventeen volunteers with chronic neuropathic pain participated in the experiment. Electrical stimuli were applied to assess the NWR-T and the EP-T. In addition, psychological factors (ie, pain characteristics, depression, anxiety, and disability indexes) were also recorded. The NWR-T and EP-T were assessed with the SCS system off (at least 8 h before the experiment), and then reassessed 1 hour after the SCS system was turned on. Results: Ongoing pain intensity ratings decreased (P = 0.018), whereas the NWR-T increased (P = 0.028) after the SCS was turned on, whereas no significant difference was found for EP-T (P = 0.324). Psychological factors were significant predictors for EP-T but not for NWR-T. Discussion: The results of this study suggest that pain relief after SCS is partially mediated by a decrease in the excitability of dorsal horn neurons in the spinal cord. Key Words: spinal cord stimulation, nociceptive withdrawal reflex, electrical pain threshold, psychological assessment
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T
he experience of pain integrates somatosensory signals (nociceptive and non-nociceptive) and the individual’s overall physical, emotional, and mental status.1–3 Whereas
Received for publication July 2, 2014; revised January 29, 2015; accepted December 20, 2014. From the *Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, School of Medicine, Aalborg University, Aalborg, Denmark; Departments of wPain and Rehabilitation Center; and zMedical and Health Sciences, Linko¨ping University, Linko¨ping, Sweden. Supported by the Swedish Research Council (K2011-69X-21874-01-6), Stockholm, Sweden, and the Swedish Council for Working Life and Social Research (2010-0913), Stockholm, Sweden. The authors declare no conflict of interest. Reprints: Jose´ A. Biurrun Manresa, PhD, Department of Health Science and Technology, Center for Sensory-Motor Interaction, School of Medicine, Aalborg University, Fredrik Bajers Vej 7, Aalborg Øst 9220, Denmark (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/AJP.0000000000000209
both acute and chronic pain are the results of integrated events on both peripheral and central levels, recent research shows that chronic pain is even more complex than acute pain due to plastic and sometimes permanent changes in the nociceptive system, among which the most predominant is widespread central hyperexcitability.4–6 Furthermore, various psychological factors interact strongly with the experience of pain in chronic conditions.3,7–9 Thus, nociceptive mechanisms identified in acute pain in healthy people are not necessarily valid for intermittent, subchronic or chronic pain. One of the neuromodulatory treatments that has been successfully applied to treat chronic pain is spinal cord stimulation (SCS). It is based on the gate control theory and its general principles of segmental pain inhibition.10 The first report of a SCS system was published in 196711; with time, it was found that the method was more effective in the management of neuropathic pain, particularly chronic back and leg pain (CBLP) and failed back surgery syndrome (FBSS).12–14 The systematic assessment of pain in humans is a challenging task, as simple questionnaires or pain intensity ratings do not reflect the pain mechanisms involved.15 Electrophysiological tests, for instance those based on the nociceptive withdrawal reflex (NWR), can be used to gain additional insight on the excitability of the spinal nociceptive system.16 These tests are objective and reliable,17,18 and may provide valuable information about the location and mechanism of the alteration in nociceptive processing.4,19,20 In particular, it has already been shown that patients with chronic pain display lower NWR thresholds (NWR-T) and enlarged reflex receptive fields (RRFs) compared with healthy volunteers.21–23 However, it is currently not known how reversible changes in the NWR are and what the timeframe is for such changes. The purpose of this study was to investigate dynamic changes in nociception and pain perception triggered by SCS in CBLP patients. Specifically, the main endpoints were: (1) to determine if there were differences in NWR-T and electrical pain thresholds (EP-T) before and after SCS and if so; (2) to establish if there was a relationship between these differences and psychological factors associated with chronic pain conditions, such as pain characteristics (locations and duration of pain), psychological stress (anxiety, depression, and catastrophizing), and level of disability.
METHODS Participants Seventeen volunteers participated in the experiment. Inclusion criteria were: age between 18 and 70 years,
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chronic neuropathic pain, specifically low-back pain with sciatica (radiation) in one or both legs (CBLP) as a result of back surgery (N = 15) or trauma (N = 2), and a SCS system implanted for pain relief. Exclusion criteria for the present study were: extensive concomitant pain problems (ie, pain intensities >7 according to the numeric rating scale (NRS) in several of the predefined anatomical areas of the upper part of the body; see below), severe cardiopulmonary disease, ongoing infection (systemically or in the lumbar region), and psychiatric illness (including substance abuse); no patients with an SCS system were excluded due to these reasons. The study was granted ethical clearance by the Linko¨ping University Ethics Committee (Dnr: 2011/283-31). Written informed consent was obtained before participation, and the Declaration of Helsinki was respected.
Questionnaire All participants answered a questionnaire in their home 1 day before the experiment. The questionnaire was delivered at arrival to the laboratory. The questionnaire covered the following areas: anthropometric data, smoking habits, pain characteristics, pain sensitivity, psychological distress (anxiety, depression, and catastrophizing), and disability. The variables and instruments used in the questionnaire are described below.
Anthropometric Data Self-reported weight and height were registered and body mass index was calculated. Participants also reported their smoking habits (yes, every day; yes, but not every day; no; no, but has earlier been a smoker).
Pain Characteristics Different aspects of pain duration were registered: pain duration for current pain condition (in years), pain duration for persistent pain (in years), if current pain was intermittent or persistent (ie, never pain free), and if the pain condition was due to a trauma (ie, duration in years). Participants reported the type of analgesics they took at the time of the experiment and the consumption level using a 5-graded scale (every day; several times a week; a few times a week; occasionally; never). Pain intensity ratings were registered using a NRS with the endpoints 0 = no pain and 10 = worst possible pain. Ten anatomic regions (shown on an outline) were selected for pain intensity assessment: (1) head, (2) neck, (3) shoulders, (4) elbows, (5) wrists/hands, (6) upper back, (7) lower back, (8) hips, (9) knees, and (10) ankles/feet. An index quantifying number of regions with pain (RPI) was also calculated, with a possible range of 0 to 10. Hence, RPI was used to indicate the degree of anatomic spreading of pain in the body.
Nociception and Pain Perception After SCS
the questionnaire was developed from the English language through translation-back translation.24,25
Hospital Anxiety and Depression Scale (HADS) The HADS is a short self-assessment questionnaire that screens for anxiety and depression.26,27 HADS comprises 7 items in each of the depression and anxiety scales (HAD-A—anxiety and HAD-D—depression). Possible subscale scores range from 0 to 21, with the lower score indicating the least depression and anxiety possible; 0 to 7 indicates no depression/anxiety, 8 to 10 indicates possible depression/anxiety, and >11 indicates presence of depression/anxiety.
The Pain Catastrophizing Scale (PCS) Catastrophizing has been shown to be a maladaptive coping strategy in relation to various measures of functioning in different patient populations.28–31 The PCS measures 3 dimensions of catastrophizing: rumination, magnification, and helplessness.32,33 For the total PCS (PCS-total) used in the present study, 52 was the maximum score. Higher scores represent worse outcomes.
Disability Rating Index (DRI) The DRI was used to assess mainly physical aspects of disability.34 The 12 items were divided into 3 sections; items 1 to 4: common basic activities of daily life; items 5 to 8: more demanding daily physical activities; items 9 to 12: work-related or more vigorous activities. The questions are arranged in increasing order of physical demand, particularly with reference to low-back pain. The DRI was calculated as the mean of the 12 items (ie, the DR-index is a continuous scale and can vary between 0 to 100; a high value denotes high disability). The items were: (1) dressing without help; (2) outdoor walks; (3) climbing stairs; (4) sitting long time; (5) standing bent over a sink; (6) carrying a bag; (7) making a bed; (8) running; (9) light work; (10) heavy work; (11) lifting heavy objects; and (12) participating in exercise/sports.
Electrical Stimulation Electrical stimulation was performed through surface electrodes to evoke the NWR. The cathode (15 15 mm, type Neuroline 700; Ambu A/S, Ballerup, Denmark) was placed in the arc of the sole of the left foot, whereas the anode was an electrode pad (50 90 mm, type Synapse; Ambu A/S) placed on the dorsum of the foot. The stimulus consisted of a constant current burst of 5 square-wave pulses, 1-ms duration, delivered at 200 Hz by a computercontrolled electrical stimulator. Electrical stimuli were delivered with a random interstimulus intervals of 10 to 15 seconds.
The Pain Sensitivity Questionnaire (PSQ)
Electromyography (EMG) Recordings
The PSQ is a self-assessment questionnaire for the evaluation of subjective pain sensitivity. It is based on pain intensity estimation of the events of common daily activities that can be associated with pain. It consists of 17 questions that are answered by an estimate on a 10-point scale where 0 is no pain, 1 is pain that is almost not noticeable, and 10 is the worst pain imaginable or believed possible. The mean value of the 17 scales is calculated and used as a measure of the subjective pain sensitivity. The instrument is reliable, has been validated for use in experimental pain and has shown good psychometric properties. A Swedish version of
The NWR was assessed by surface EMG recordings of the tibialis anterior muscle. The skin was initially shaved and cleaned with isopropyl alcohol, and afterwards 2 electrodes (30 22 mm, type Neuroline 720; Ambu A/S) were placed over the muscle belly, separated by 20 mm (centerto-center distance), at 1/3 on the line between the tip of the fibula and the tip of the medial malleolus in the direction of the line between the tip of the fibula and the tip of the medial malleolus. The ground was an electrode pad (50 90 mm, type Synapse; Ambu A/S) placed over the left bony prominence of the anterior superior iliac spine. EMG
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Statistical analyses were made using IBM SPSS (version 21.0; IBM Corporation, NY) and SIMCA-P +
(version 13.0; Umetrics Inc., Umea˚, Sweden) and P < 0.05 was used as level of significance in all analyses. Data are presented as mean ± SD unless otherwise specified. Paired t test were used to test for differences in the NWR-T, EP-T, and ongoing pain intensity ratings before and after SCS. Principal component analysis (PCA) and partial least squares or projection to latent structures (PLS-OPLS/ O2PLS) were used to investigate the multivariate correlation patterns between NWR-T, EP-T and anthropometric data, pain intensities, subjective pain sensitivity, psychological symptoms, and disability using SIMCA-P + .37 These methods can be applied in situations with low subjects-to-variables ratios.38,39 PCA can be viewed as a multivariate correlation analyses. The main reason for using PCA in the present study was to identify multivariate outliers. Variables loading upon the same component (p) are positively correlated, and variables with high loadings but with different signs are negatively correlated. Variables with high absolute loadings with respect to the component under consideration were considered significant.37 The obtained significant components are per definition not correlated. R2 describes the goodness of fit.37 PLS-OPLS/O2PLS was used for the multivariate regression analysis of NWR-T and EPT using anthropometric data, pain intensities, subjective pain sensitivity, psychological symptoms, and disability as regressors.37 The VIP variable (variable influence on projection) indicates the relative relevance of each regressor (X) variable. VIPZ1.0 was considered significant. Coefficients were used to note the direction of the relationship (positive or negative). VIP values are reported in descending order and the sign of the coefficient is also given. Multiple linear regression (MLR) is an alternative method for regression analysis, but it assumes that the X variables are independent. If multicollinearity (ie, high correlations) occurs among the X variables in MLR, the regression coefficients become unstable and their interpretability breaks down. MLR also assumes that a high subject-to-variables ratio is present (eg, >5) and such requirements are not required for PLS. As mentioned above, PLS can handle subject-to-variables ratios 12. The stimulation intensity is then decreased until the NWR is no longer evoked, assessed as a z score 12 indicated that the NWR was evoked, so the stimulation intensity was then decreased until the NWR disappeared (z score 1.0). The sign of coefficient indicate the direction of the correlation. The bottom row displays the explained variation (R2). Raw data for the regressors are presented in Table 1 and in text. BMI indicates body mass index; DRI, Disability Rating Index; HAD-A, Anxiety subscale of Hospital Anxiety and Depression Scale; HAD-D, Depression subscale of Hospital Anxiety and Depression Scale; NRS, pain intensity according to the numeric rating scale; PCS, Pain Catastrophizing Scale; PSQ, Pain Sensitivity Questionnaire; RPI, number of regions with pain.
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change in pain intensity rating, and improvements in quality of life and functional capacity. An alternative approach is to use mechanistic pain biomarkers to understand the mechanisms underlying the effect of SCS, such as changes in pain ratings to painful cutaneous heat47 or somatosensory-evoked potentials.48 In this regard, the NWR, may be used.16–18 A number of studies have demonstrated that the NWR is a valid mechanistic biomarker for several pain conditions: lower NWR-T and/or enlarged RRF areas have been documented in patients with whiplash injury and fibromyalgia,23 endometriosis,22 chronic neck pain, and acute and chronic low-back pain.21 Furthermore, it was previously demonstrated that the NWR could successfully reflect pain sensitivity changes during epidural and transcutaneous analgesic neurostimulation in patients with chronic intractable pain.49 In this regard, patients with CBLP and an implanted SCS system present a unique opportunity to study dynamic changes in nociception (assessed by the NWR) and its association with pain perception in a situation in which the patients were not stimulated (ie, experiencing severe ongoing pain) and compare it to the situation in which the patients were just stimulated (ie, experiencing a reduction in ongoing pain). As hypothesized, the results of this study showed that the NWR-T was significantly increased 1 hour after the SCS was turned on, with an average difference of 2.7 ± 4.0 mA compared with the baseline condition. Furthermore, this difference could not be explained by any of the recorded factors, that is, anthropometric data, pain intensity ratings, subjective pain sensitivity, psychological symptoms, or disability indexes. In contrast, the EP-T with and without SCS was switched on correlated negatively with habitual pain intensities in several anatomic regions (eg, lower back, hips, wrists/hands, neck), spreading of pain (RPI), depressive symptoms, and whether the patients were smokers/nonsmokers (Table 2). Hence, these analyses demonstrate the influence of subjective aspects upon the EP-T. Nevertheless, a significant difference in EP-T due to SCS could not be detected. The present results are in line with previous studies, which showed that NWR-T ranks among the best measures in terms of discriminative ability to detect pain hypersensitivity in chronic pain patients.50 Moreover, sudden changes in spinal nociception are rapidly detected by the NWR whether they develop in the span of hours (as it is the case in the present study) or even minutes, as demonstrated in surrogate models of central sensitization assessed with the NWR.51–53 Furthermore, this study also verified that NWRT cannot be predicted by psychological factors. In general, NWR outcomes are not influenced by depression, anxiety, or catastrophizing,21,22,54,55 and they are not correlated to outcomes from other sensory modalities (eg, thermal, mechanical) in experimental pain assessment either.56 However, there are some reports that NWR measures in general (eg, NWR-T, RRF areas) can also be modulated by supraspinal activity, for example, affective or cognitive processes,57–60 which is why the experimental conditions need to be carefully controlled to obtain valid and reliable outcomes. In the light of this evidence, the NWR can be regarded as a valid measure of the excitability of the nociceptive system at spinal level. Furthermore, the lower NWR-T observed in the present study in the absence of SCS most likely reflect a state of spinal hyperexcitability, probably as a consequence of an increase in the number of responsive neurons or an increase in synaptic efficacy that leads to an expansion of neuronal receptive fields Copyright
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(particularly wide-dynamic-range neurons).61,62 This might indicate that the mechanisms behind SCS efficiency is linked to a reduction of the excitability of the dorsal horn neurons. Unlike previous experiments, however, it was not possible to show any differences in the EP-T in response to SCS. Interestingly, EP-T were relatively low (an average of 3.2 ± 1.5 mA at the first assessment) compared with other experiments with similar setups and previously published reference values for pain-free volunteers.18,21,22,55,63 At those levels of stimulation intensity, it is possible that the nociceptors were not yet activated, and the subjective thresholds simply reflect a state of allodynia. In any case, the very small EP-T values recorded did not have enough discriminative power to reflect differences in subjective pain perception (floor effect). Several studies have shown a similar dissociation between the NWR and subjective pain perception before, which reinforces the idea that pain is a complex, multidimensional process and that single outcome measures can only partially describe its effects and underlying mechanisms.56,64–66 Finally, it is worth mentioning that all participants included in the present study were SCS responders to be able to investigate the dynamic changes in nociception and pain perception triggered by SCS. In future studies, it would be interesting to investigate if responder and nonresponders of a trial of SCS before implantation differ with respect to NWR-T and EP-T. In conclusion, the results of this study demonstrated that the NWR-T is significantly increased 1 hour after SCS is initiated in patients with CBLP. These results support the notion that pain relief after SCS is partially mediated by a decrease in the excitability of dorsal horn neurons in the spinal cord. ACKNOWLEDGMENTS The authors acknowledge research nurse Anna-Carin Sandell , Council of O¨stergo¨tland, Linko¨ping, Sweden; for her valuable help during the experiment. REFERENCES 1. Khalsa PS. Biomechanics of musculoskeletal pain: dynamics of the neuromatrix. J Electromyogr Kinesiol. 2004;14:109–120. 2. Porro CA. Functional imaging and pain: behavior, perception, and modulation. Neuroscientist. 2003;9:354–369. 3. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–1768. 4. Desmeules JA, Cedraschi C, Rapiti E, et al. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum. 2003;48:1420–1429. 5. Curatolo M, Petersen-Felix S, Arendt-Nielsen L, et al. Central hypersensitivity in chronic pain after whiplash injury. Clin J Pain. 2001;17:306–315. 6. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926. 7. Grachev ID, Fredrickson BE, Apkarian AV. Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study. Pain. 2000;89:7–18. 8. Petersen-Felix S, Curatolo M. Neuroplasticity—an important factor in acute and chronic pain. Swiss Med Wkly. 2002;132: 273–278. 9. Wilder-Smith OHG, Tassonyi E, Arendt-Nielsen L. Preoperative back pain is associated with diverse manifestations of central neuroplasticity. Pain. 2002;97:189–194. 10. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150:971–979.
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Dynamic Changes in Nociception and Pain Perception After Spinal Cord Stimulation in Chronic Neuropathic Pain Patients Jose´ A. Biurrun Manresa, PhD,* Jan So¨rensen, MD, PhD,wz Ole K. Andersen, PhD, dr scient,* Lars Arendt-Nielsen, PhD, dr scient med,* and Bjo¨rn Gerdle, MD, PhDwz
Objectives: Patients with an implanted spinal cord stimulation (SCS) system for pain management present an opportunity to study dynamic changes in the pain system in a situation where patients are not stimulated (ie, experiencing severe pain) compared with a situation in which patients have just been stimulated (ie, pain free or greatly reduced pain). The aims of this study were (1) to determine if there are differences in nociceptive withdrawal reflex thresholds (NWR-T) and electrical pain thresholds (EP-T) before and after SCS; and (2) to establish if these differences are related to psychological factors associated with chronic pain. Methods: Seventeen volunteers with chronic neuropathic pain participated in the experiment. Electrical stimuli were applied to assess the NWR-T and the EP-T. In addition, psychological factors (ie, pain characteristics, depression, anxiety, and disability indexes) were also recorded. The NWR-T and EP-T were assessed with the SCS system off (at least 8 h before the experiment), and then reassessed 1 hour after the SCS system was turned on. Results: Ongoing pain intensity ratings decreased (P = 0.018), whereas the NWR-T increased (P = 0.028) after the SCS was turned on, whereas no significant difference was found for EP-T (P = 0.324). Psychological factors were significant predictors for EP-T but not for NWR-T. Discussion: The results of this study suggest that pain relief after SCS is partially mediated by a decrease in the excitability of dorsal horn neurons in the spinal cord. Key Words: spinal cord stimulation, nociceptive withdrawal reflex, electrical pain threshold, psychological assessment
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T
he experience of pain integrates somatosensory signals (nociceptive and non-nociceptive) and the individual’s overall physical, emotional, and mental status.1–3 Whereas
Received for publication July 2, 2014; revised January 29, 2015; accepted December 20, 2014. From the *Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, School of Medicine, Aalborg University, Aalborg, Denmark; Departments of wPain and Rehabilitation Center; and zMedical and Health Sciences, Linko¨ping University, Linko¨ping, Sweden. Supported by the Swedish Research Council (K2011-69X-21874-01-6), Stockholm, Sweden, and the Swedish Council for Working Life and Social Research (2010-0913), Stockholm, Sweden. The authors declare no conflict of interest. Reprints: Jose´ A. Biurrun Manresa, PhD, Department of Health Science and Technology, Center for Sensory-Motor Interaction, School of Medicine, Aalborg University, Fredrik Bajers Vej 7, Aalborg Øst 9220, Denmark (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/AJP.0000000000000209
both acute and chronic pain are the results of integrated events on both peripheral and central levels, recent research shows that chronic pain is even more complex than acute pain due to plastic and sometimes permanent changes in the nociceptive system, among which the most predominant is widespread central hyperexcitability.4–6 Furthermore, various psychological factors interact strongly with the experience of pain in chronic conditions.3,7–9 Thus, nociceptive mechanisms identified in acute pain in healthy people are not necessarily valid for intermittent, subchronic or chronic pain. One of the neuromodulatory treatments that has been successfully applied to treat chronic pain is spinal cord stimulation (SCS). It is based on the gate control theory and its general principles of segmental pain inhibition.10 The first report of a SCS system was published in 196711; with time, it was found that the method was more effective in the management of neuropathic pain, particularly chronic back and leg pain (CBLP) and failed back surgery syndrome (FBSS).12–14 The systematic assessment of pain in humans is a challenging task, as simple questionnaires or pain intensity ratings do not reflect the pain mechanisms involved.15 Electrophysiological tests, for instance those based on the nociceptive withdrawal reflex (NWR), can be used to gain additional insight on the excitability of the spinal nociceptive system.16 These tests are objective and reliable,17,18 and may provide valuable information about the location and mechanism of the alteration in nociceptive processing.4,19,20 In particular, it has already been shown that patients with chronic pain display lower NWR thresholds (NWR-T) and enlarged reflex receptive fields (RRFs) compared with healthy volunteers.21–23 However, it is currently not known how reversible changes in the NWR are and what the timeframe is for such changes. The purpose of this study was to investigate dynamic changes in nociception and pain perception triggered by SCS in CBLP patients. Specifically, the main endpoints were: (1) to determine if there were differences in NWR-T and electrical pain thresholds (EP-T) before and after SCS and if so; (2) to establish if there was a relationship between these differences and psychological factors associated with chronic pain conditions, such as pain characteristics (locations and duration of pain), psychological stress (anxiety, depression, and catastrophizing), and level of disability.
METHODS Participants Seventeen volunteers participated in the experiment. Inclusion criteria were: age between 18 and 70 years,
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chronic neuropathic pain, specifically low-back pain with sciatica (radiation) in one or both legs (CBLP) as a result of back surgery (N = 15) or trauma (N = 2), and a SCS system implanted for pain relief. Exclusion criteria for the present study were: extensive concomitant pain problems (ie, pain intensities >7 according to the numeric rating scale (NRS) in several of the predefined anatomical areas of the upper part of the body; see below), severe cardiopulmonary disease, ongoing infection (systemically or in the lumbar region), and psychiatric illness (including substance abuse); no patients with an SCS system were excluded due to these reasons. The study was granted ethical clearance by the Linko¨ping University Ethics Committee (Dnr: 2011/283-31). Written informed consent was obtained before participation, and the Declaration of Helsinki was respected.
Questionnaire All participants answered a questionnaire in their home 1 day before the experiment. The questionnaire was delivered at arrival to the laboratory. The questionnaire covered the following areas: anthropometric data, smoking habits, pain characteristics, pain sensitivity, psychological distress (anxiety, depression, and catastrophizing), and disability. The variables and instruments used in the questionnaire are described below.
Anthropometric Data Self-reported weight and height were registered and body mass index was calculated. Participants also reported their smoking habits (yes, every day; yes, but not every day; no; no, but has earlier been a smoker).
Pain Characteristics Different aspects of pain duration were registered: pain duration for current pain condition (in years), pain duration for persistent pain (in years), if current pain was intermittent or persistent (ie, never pain free), and if the pain condition was due to a trauma (ie, duration in years). Participants reported the type of analgesics they took at the time of the experiment and the consumption level using a 5-graded scale (every day; several times a week; a few times a week; occasionally; never). Pain intensity ratings were registered using a NRS with the endpoints 0 = no pain and 10 = worst possible pain. Ten anatomic regions (shown on an outline) were selected for pain intensity assessment: (1) head, (2) neck, (3) shoulders, (4) elbows, (5) wrists/hands, (6) upper back, (7) lower back, (8) hips, (9) knees, and (10) ankles/feet. An index quantifying number of regions with pain (RPI) was also calculated, with a possible range of 0 to 10. Hence, RPI was used to indicate the degree of anatomic spreading of pain in the body.
Nociception and Pain Perception After SCS
the questionnaire was developed from the English language through translation-back translation.24,25
Hospital Anxiety and Depression Scale (HADS) The HADS is a short self-assessment questionnaire that screens for anxiety and depression.26,27 HADS comprises 7 items in each of the depression and anxiety scales (HAD-A—anxiety and HAD-D—depression). Possible subscale scores range from 0 to 21, with the lower score indicating the least depression and anxiety possible; 0 to 7 indicates no depression/anxiety, 8 to 10 indicates possible depression/anxiety, and >11 indicates presence of depression/anxiety.
The Pain Catastrophizing Scale (PCS) Catastrophizing has been shown to be a maladaptive coping strategy in relation to various measures of functioning in different patient populations.28–31 The PCS measures 3 dimensions of catastrophizing: rumination, magnification, and helplessness.32,33 For the total PCS (PCS-total) used in the present study, 52 was the maximum score. Higher scores represent worse outcomes.
Disability Rating Index (DRI) The DRI was used to assess mainly physical aspects of disability.34 The 12 items were divided into 3 sections; items 1 to 4: common basic activities of daily life; items 5 to 8: more demanding daily physical activities; items 9 to 12: work-related or more vigorous activities. The questions are arranged in increasing order of physical demand, particularly with reference to low-back pain. The DRI was calculated as the mean of the 12 items (ie, the DR-index is a continuous scale and can vary between 0 to 100; a high value denotes high disability). The items were: (1) dressing without help; (2) outdoor walks; (3) climbing stairs; (4) sitting long time; (5) standing bent over a sink; (6) carrying a bag; (7) making a bed; (8) running; (9) light work; (10) heavy work; (11) lifting heavy objects; and (12) participating in exercise/sports.
Electrical Stimulation Electrical stimulation was performed through surface electrodes to evoke the NWR. The cathode (15 15 mm, type Neuroline 700; Ambu A/S, Ballerup, Denmark) was placed in the arc of the sole of the left foot, whereas the anode was an electrode pad (50 90 mm, type Synapse; Ambu A/S) placed on the dorsum of the foot. The stimulus consisted of a constant current burst of 5 square-wave pulses, 1-ms duration, delivered at 200 Hz by a computercontrolled electrical stimulator. Electrical stimuli were delivered with a random interstimulus intervals of 10 to 15 seconds.
The Pain Sensitivity Questionnaire (PSQ)
Electromyography (EMG) Recordings
The PSQ is a self-assessment questionnaire for the evaluation of subjective pain sensitivity. It is based on pain intensity estimation of the events of common daily activities that can be associated with pain. It consists of 17 questions that are answered by an estimate on a 10-point scale where 0 is no pain, 1 is pain that is almost not noticeable, and 10 is the worst pain imaginable or believed possible. The mean value of the 17 scales is calculated and used as a measure of the subjective pain sensitivity. The instrument is reliable, has been validated for use in experimental pain and has shown good psychometric properties. A Swedish version of
The NWR was assessed by surface EMG recordings of the tibialis anterior muscle. The skin was initially shaved and cleaned with isopropyl alcohol, and afterwards 2 electrodes (30 22 mm, type Neuroline 720; Ambu A/S) were placed over the muscle belly, separated by 20 mm (centerto-center distance), at 1/3 on the line between the tip of the fibula and the tip of the medial malleolus in the direction of the line between the tip of the fibula and the tip of the medial malleolus. The ground was an electrode pad (50 90 mm, type Synapse; Ambu A/S) placed over the left bony prominence of the anterior superior iliac spine. EMG
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Statistical analyses were made using IBM SPSS (version 21.0; IBM Corporation, NY) and SIMCA-P +
(version 13.0; Umetrics Inc., Umea˚, Sweden) and P < 0.05 was used as level of significance in all analyses. Data are presented as mean ± SD unless otherwise specified. Paired t test were used to test for differences in the NWR-T, EP-T, and ongoing pain intensity ratings before and after SCS. Principal component analysis (PCA) and partial least squares or projection to latent structures (PLS-OPLS/ O2PLS) were used to investigate the multivariate correlation patterns between NWR-T, EP-T and anthropometric data, pain intensities, subjective pain sensitivity, psychological symptoms, and disability using SIMCA-P + .37 These methods can be applied in situations with low subjects-to-variables ratios.38,39 PCA can be viewed as a multivariate correlation analyses. The main reason for using PCA in the present study was to identify multivariate outliers. Variables loading upon the same component (p) are positively correlated, and variables with high loadings but with different signs are negatively correlated. Variables with high absolute loadings with respect to the component under consideration were considered significant.37 The obtained significant components are per definition not correlated. R2 describes the goodness of fit.37 PLS-OPLS/O2PLS was used for the multivariate regression analysis of NWR-T and EPT using anthropometric data, pain intensities, subjective pain sensitivity, psychological symptoms, and disability as regressors.37 The VIP variable (variable influence on projection) indicates the relative relevance of each regressor (X) variable. VIPZ1.0 was considered significant. Coefficients were used to note the direction of the relationship (positive or negative). VIP values are reported in descending order and the sign of the coefficient is also given. Multiple linear regression (MLR) is an alternative method for regression analysis, but it assumes that the X variables are independent. If multicollinearity (ie, high correlations) occurs among the X variables in MLR, the regression coefficients become unstable and their interpretability breaks down. MLR also assumes that a high subject-to-variables ratio is present (eg, >5) and such requirements are not required for PLS. As mentioned above, PLS can handle subject-to-variables ratios 12. The stimulation intensity is then decreased until the NWR is no longer evoked, assessed as a z score 12 indicated that the NWR was evoked, so the stimulation intensity was then decreased until the NWR disappeared (z score 1.0). The sign of coefficient indicate the direction of the correlation. The bottom row displays the explained variation (R2). Raw data for the regressors are presented in Table 1 and in text. BMI indicates body mass index; DRI, Disability Rating Index; HAD-A, Anxiety subscale of Hospital Anxiety and Depression Scale; HAD-D, Depression subscale of Hospital Anxiety and Depression Scale; NRS, pain intensity according to the numeric rating scale; PCS, Pain Catastrophizing Scale; PSQ, Pain Sensitivity Questionnaire; RPI, number of regions with pain.
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change in pain intensity rating, and improvements in quality of life and functional capacity. An alternative approach is to use mechanistic pain biomarkers to understand the mechanisms underlying the effect of SCS, such as changes in pain ratings to painful cutaneous heat47 or somatosensory-evoked potentials.48 In this regard, the NWR, may be used.16–18 A number of studies have demonstrated that the NWR is a valid mechanistic biomarker for several pain conditions: lower NWR-T and/or enlarged RRF areas have been documented in patients with whiplash injury and fibromyalgia,23 endometriosis,22 chronic neck pain, and acute and chronic low-back pain.21 Furthermore, it was previously demonstrated that the NWR could successfully reflect pain sensitivity changes during epidural and transcutaneous analgesic neurostimulation in patients with chronic intractable pain.49 In this regard, patients with CBLP and an implanted SCS system present a unique opportunity to study dynamic changes in nociception (assessed by the NWR) and its association with pain perception in a situation in which the patients were not stimulated (ie, experiencing severe ongoing pain) and compare it to the situation in which the patients were just stimulated (ie, experiencing a reduction in ongoing pain). As hypothesized, the results of this study showed that the NWR-T was significantly increased 1 hour after the SCS was turned on, with an average difference of 2.7 ± 4.0 mA compared with the baseline condition. Furthermore, this difference could not be explained by any of the recorded factors, that is, anthropometric data, pain intensity ratings, subjective pain sensitivity, psychological symptoms, or disability indexes. In contrast, the EP-T with and without SCS was switched on correlated negatively with habitual pain intensities in several anatomic regions (eg, lower back, hips, wrists/hands, neck), spreading of pain (RPI), depressive symptoms, and whether the patients were smokers/nonsmokers (Table 2). Hence, these analyses demonstrate the influence of subjective aspects upon the EP-T. Nevertheless, a significant difference in EP-T due to SCS could not be detected. The present results are in line with previous studies, which showed that NWR-T ranks among the best measures in terms of discriminative ability to detect pain hypersensitivity in chronic pain patients.50 Moreover, sudden changes in spinal nociception are rapidly detected by the NWR whether they develop in the span of hours (as it is the case in the present study) or even minutes, as demonstrated in surrogate models of central sensitization assessed with the NWR.51–53 Furthermore, this study also verified that NWRT cannot be predicted by psychological factors. In general, NWR outcomes are not influenced by depression, anxiety, or catastrophizing,21,22,54,55 and they are not correlated to outcomes from other sensory modalities (eg, thermal, mechanical) in experimental pain assessment either.56 However, there are some reports that NWR measures in general (eg, NWR-T, RRF areas) can also be modulated by supraspinal activity, for example, affective or cognitive processes,57–60 which is why the experimental conditions need to be carefully controlled to obtain valid and reliable outcomes. In the light of this evidence, the NWR can be regarded as a valid measure of the excitability of the nociceptive system at spinal level. Furthermore, the lower NWR-T observed in the present study in the absence of SCS most likely reflect a state of spinal hyperexcitability, probably as a consequence of an increase in the number of responsive neurons or an increase in synaptic efficacy that leads to an expansion of neuronal receptive fields Copyright
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(particularly wide-dynamic-range neurons).61,62 This might indicate that the mechanisms behind SCS efficiency is linked to a reduction of the excitability of the dorsal horn neurons. Unlike previous experiments, however, it was not possible to show any differences in the EP-T in response to SCS. Interestingly, EP-T were relatively low (an average of 3.2 ± 1.5 mA at the first assessment) compared with other experiments with similar setups and previously published reference values for pain-free volunteers.18,21,22,55,63 At those levels of stimulation intensity, it is possible that the nociceptors were not yet activated, and the subjective thresholds simply reflect a state of allodynia. In any case, the very small EP-T values recorded did not have enough discriminative power to reflect differences in subjective pain perception (floor effect). Several studies have shown a similar dissociation between the NWR and subjective pain perception before, which reinforces the idea that pain is a complex, multidimensional process and that single outcome measures can only partially describe its effects and underlying mechanisms.56,64–66 Finally, it is worth mentioning that all participants included in the present study were SCS responders to be able to investigate the dynamic changes in nociception and pain perception triggered by SCS. In future studies, it would be interesting to investigate if responder and nonresponders of a trial of SCS before implantation differ with respect to NWR-T and EP-T. In conclusion, the results of this study demonstrated that the NWR-T is significantly increased 1 hour after SCS is initiated in patients with CBLP. These results support the notion that pain relief after SCS is partially mediated by a decrease in the excitability of dorsal horn neurons in the spinal cord. ACKNOWLEDGMENTS The authors acknowledge research nurse Anna-Carin Sandell , Council of O¨stergo¨tland, Linko¨ping, Sweden; for her valuable help during the experiment. REFERENCES 1. Khalsa PS. Biomechanics of musculoskeletal pain: dynamics of the neuromatrix. J Electromyogr Kinesiol. 2004;14:109–120. 2. Porro CA. Functional imaging and pain: behavior, perception, and modulation. Neuroscientist. 2003;9:354–369. 3. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–1768. 4. Desmeules JA, Cedraschi C, Rapiti E, et al. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum. 2003;48:1420–1429. 5. Curatolo M, Petersen-Felix S, Arendt-Nielsen L, et al. Central hypersensitivity in chronic pain after whiplash injury. Clin J Pain. 2001;17:306–315. 6. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926. 7. Grachev ID, Fredrickson BE, Apkarian AV. Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study. Pain. 2000;89:7–18. 8. Petersen-Felix S, Curatolo M. Neuroplasticity—an important factor in acute and chronic pain. Swiss Med Wkly. 2002;132: 273–278. 9. Wilder-Smith OHG, Tassonyi E, Arendt-Nielsen L. Preoperative back pain is associated with diverse manifestations of central neuroplasticity. Pain. 2002;97:189–194. 10. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150:971–979.
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