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Publicly Available Published by De Gruyter January 1, 2016

Plasma pro-inflammatory markers in chronic neuropathic pain: A multivariate, comparative, cross-sectional pilot study

  • Emmanuel Bäckryd EMAIL logo , Bijar Ghafouri , Britt Larsson and Björn Gerdle

Abstract

Background

Caused by a lesion or disease of the somatosensory system, neuropathic pain is notoriously difficult to treat with conventional analgesics. It has been suggested that inflammatory cytokines play a role in the development and maintenance of neuropathic pain. But human studies of these substances are relatively few and partly contradictory.

Objectives

To simultaneously investigate the plasma levels of chemokine interleukin 8 (IL-8) and the cytokines IL-6, IL-1 β, and Granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with peripheral neuropathic pain (most of whom due to failed back surgery syndrome) (n = 14) compared to controls (n = 17).

Results

IL-6 was significantly higher in patients than in controls (0.92 ± 0.12 pg/ml vs. 0.57 ± 0.08 pg/ml, p = 0.012). IL-1 ß, IL-8, and GM-CSF levels did not differ between the two groups. A multivariate analysis showed a tendency for patients also to have higher GM-CSF plasma levels than controls.

Conclusions

This study found an increased level of IL-6 in plasma in patients with neuropathic pain, but not for the other pro-inflammatory substances investigated. There are several possible confounders not registered or controlled for in this and other studies of neuropathic pain.

Implications

Larger studies that take several possible confounders into consideration are needed to further investigate the levels of plasma cytokines in different pain conditions.

1 Introduction

Surgical procedures involving injury to nerves are associated with a high incidence of chronic postsurgical pain (CPSP) [39]. For example, thoracotomy often leads to nerve damage due to the use of rib retractors, and the prevalence of CPSP for this surgical procedure is as high as 30-40% [16,39]. Although intra-operative nerve injury in most cases seems to be necessary for the development of CPSP, it is not by itself a sufficient cause. Other known risk factors are genetic susceptibility, preceding pain, psychosocial factors, age, and sex [16].

Neuropathic pain, defined as pain caused by a lesion or disease of the somatosensory system [14], is notoriously difficult to treat with available analgesics. Evidence-based guidelines emphasise the use of topical lidocaine, certain antidepressants (e.g., tricyclics and duloxetine), gabapentinoids and possibly opioids [7]. If better treatment strategies are to be developed, then the pathophysio-logy of different neuropathic pain conditions needs to be better understood.

Animal experiments have shown that nerve injury leads to recruitment and activation of immune cells and the secretion of Tumour Necrosis Factor (TNF, previously known as TNF-α), Interleukin 1 beta (IL-1ß), and Interleukin 6 (IL-6) by Schwann cells and macrophages [6]. Cytokines are small intracellular regulatory proteins with a molecular weight ranging between 8 and 40,000 Da [29,30]. Cytokines and chemokines sensitise peripheral nociceptors and trigger ectopic activity in primary afferents [2,31], but they may also cross the blood brain barrier and participate in central sensitisation processes in the spinal cord [38]. Blockage of IL-6 and TNF by pharmacological methods prevents neuropathic pain in neuropathic pain models [28,42]. Human studies of these substances in neuropathic pain conditions are relatively few and partly contradictory. The roles of these substances in humans are less clear [6].

This study, which compares patients with peripheral neuropathic pain (mainly failed back surgery syndrome with radiculopathy) to healthy controls, investigated the plasma levels of the pro-inflammatory chemokine interleukin 8 (IL-8) and five cytokines: TNF, IL-4, IL-6, IL-1ß, and Granulocyte macrophage colony-stimulating factor (GM-CSF) [1,32]. To detect combination patterns, we used advanced multivariate statistics as a complement to basic statistical tests.

2 Material and methods

2.1 Patients

All 14 pain patients included in this study participated in an on-going clinical trial of intrathecal bolus injections of the analgesic ziconotide (data not presented in the present paper). The following inclusion criteria were used: (1) the patient was at least 18 years of age, suffering from chronic (≥6 months) neuropathic pain due to trauma or surgery, and not responding to conventional pharmacological treatment; (2) the patient had an average Visual Analogue Scale Pain Intensity (VASPI ranging from 0 to 100 mm) the previous week ≥40mm; (3) the patient was capable to understand information regarding the study; and (4) the patient provided signed informed consent. The following exclusion criteria were used: (1) limited life expectancy (investigator’s judgement); (2) intrathecal chemotherapy; (3) known or suspected intracranial hypertension; (4) known liver or kidney disease, defined as serum transaminases, total bilirubin, alkaline phosphatase, or creati-nine >1.2 times the upper limit of normal range; (5) advanced cardio-pulmonary disease (investigator’sjudgement); (6) on-going infection, whether systemically or locally in the lumbar area; (7) coagulopathy (including medication with warfarin, clopidogrel, and heparin); (8) allergy to ziconotide or any of the excipients in the ziconotide vial; (9) history of psychiatric disorders that in the investigator’s opinion would put the patient at risk; (10) pregnant or lactating women; and (11) participation in another clinical trial during the last 30 days.

After informed consent, the following data were collected: basic demographic data; pain diagnosis; pain duration (since debut of the actual neuropathic pain condition); present and past medical history; and concomitant medication. A physical examination was performed. See Table 1 for patient characteristics and comparisons with healthy controls.

Table 1

Sociodemographic and clinical data of patients and healthy controls. Unless stated otherwise, data are presented as mean ± SEM. Furthest to the right is the result of the statistical comparisons between patients and healthy controls.

Patients (n = 14) Healthy controls (n = 17) Statistics (p-value)
Age (years) 57±3 31±3 <0.001[*]
Sex(% female) 43% 35% 0.667
Body Mass Index (kg/m2) 25.8 ±0.9 24.1 ±0.6 0.109
Pain duration (months) 92 ±20 0 0.001[*]
Pain intensity (0-100 mm)[a] 67 ±4 0 0.001[*]
Opioid dose[b](mg/day) (median, range)
% using opioids 43% 0% 0.004[*]
% using tricyclics or duloxetine 36% 0% 0.012[*]
% using gabapentinoids 36% 0% 0.012[*]
% using paracetamol 50% 0% 0.001[*]
% using NSAID[c] 7% 0% 0.452

2.2 Healthy controls

Nineteen healthy controls were recruited by local advertisement at the Faculty of Health Sciences, Linköping University, Sweden and by contacting healthy subjects from earlier studies. After informed consent, a structured interview was conducted to ensure the absence of any significant medical condition. The following areas were specifically assessed in the interview: earlier major trauma; back, joints, muscles or skeletal disease; heart or vascular disease; lung or bronchial disease; psychiatric symptoms; neurological, ear or eye disease; digestive tract disease; kidney, urinary or genital disease; skin disease; tumour or cancer; endocrine disease; haematological disease; birth defects; other disease, disability or allergy. Moreover, the presence of a known bleeding disorder was specifically inquired for. The absence of a chronic pain condition was ensured by a structured questionnaire covering sociodemographic data, presence of pain now, location of pain now, generalisation of pain, presence of intermittent pain, duration of persistent pain. The questionnaire also covered anxiety and depressive symptomatology, coping aspects and health-related quality of life aspects in order to ensure that the controls were healthy. Subjects were also given the possibility to make a pain drawing. A brief medical examination was performed, including assessment for fibromyalgia tender points.

2.3 Ethics

The healthy controls protocol was approved by the Regional Ethics Committee in Linköping (RECL), Sweden (Dnr M136-06 and Dnr 2012/94-32). The clinical trial, from which patient data were derived, was conjointly approved by the Swedish Medical Products Agency (EudraCT 2010-018920-21) and by the RECL (Dnr 2011/48-31). The clinical trial was monitored by the Linköping Academic Research Centre (LARC) and was conducted according to the standards of Good Clinical Practice (GCP).

2.4 Analytical methods

For every subject in this study prior to the clinical trial of ziconotide, a 10-ml venous blood sample was drawn into an EDTA tube. The samples were immediately cooled on ice and transported to the Painomics® laboratory, Linköping University Hospital, where they were centrifuged for 10min at 1000 × g within 30 min of blood collection. Plasma was then removed, aliquoted, and stored at -70 °C until analysis.

Plasma samples (50 μl) were analysed in the Luminex 200 instrument (Life Technologies, Invitrogen Stockholm, Sweden) using a human cytokine 6-plex antibody bead kit (R&D Systems Europe Ltd, UK) for the assessment of IL-1 β, IL-4, IL-6, IL-8, GM-CSF, and TNF. The concentrations were calculated by reference to a seven-point five-parameter logistic standard curve for each substance using MasterPlex QT 2010 (MiraiBio Inc., San Diego, CA, USA).

2.5 Statistics

For basic statistics, the IBM Statistical Package for the Social Sciences (SPSS, IBM Corporation, Somers, New York, USA) version 21.0 was used. Unless stated otherwise, data are reported as mean ± SEM in the text and in tables. For comparisons between groups, the Mann Whitney U test or, for categorical data, the Chi-square test or Fisher’s exact test was performed. Spearman’s non-parametric rank correlation coefficient (rs) was calculated for correlation analysis of non-parametric data. p ≤ 0.05 was considered significant in all statistical tests.

When simultaneously investigating several cytokines or other algesic substances in pain conditions in humans, statistical analyses typically compute each substance separately [3,12,22,37]. Although simple, this multiple testing approach could increase the risk of Type I errors (false positive findings) [33]. Basic statistical methods can quantify level changes of individual substances but not inter-relationships amongst them and thereby ignore system-wide aspects [13]. Basic classical methods also assume variable independence when interpreting the results [27]. To handle these drawbacks, a multi/megavariate regression method was used [11]. Hence, for multivariate/megavariate analyses, SIMCA-P+ version 13.0 (Umetrics AB, Umeå, Sweden) was used.

Principal Component Analysis (PCA) was used to extract and display systematic variation in the data matrix. All variables were log transformed prior to statistical analysis if necessary. A cross validation technique was used to identify nontrivial components. Variables loading upon the same component are correlated and variables with high loadings but with different signs are negatively correlated. Variables with high loadings were considered significant. Hence, the most important of these were those with high absolute loadings. Significant variables with high loadings (positive or negative) are more important for the component under consideration than variables with lower absolute loadings. In the present study, PCA was used to check for multivariate outliers. Outliers were identified using the two powerful methods available in SIMCA-P+: (1) score plots in combination with Hotelling’s T2 (identifies strong outliers) and (2) distance to model in X-space (identifies moderate outliers). No multivariate outliers were found in the present study.

Partial Least Square Regression (PLS) (i.e., PLS-OPLS/O2PLS) was used for multivariate regression analysis. The importance of the variables is measured as a Variable Influence on Projection (VIP) value. This indicates the relevance of each X-variable pooled over all dimensions and Y-variables; the group of variables that best explain Y. VIP >1.0 was considered significant. Coefficients (PLS scaled and centred regression coefficients; coeffcs) were used to note the direction of the relationship (positive or negative correlation). Multiple linear regression (MLR) or logistic regression (LR) could possibly have been alternatives in the regressions, but these methods assume that the regressor (X) variables are fairly independent. If multi-collinearity (i.e., high correlations) occurs among the X-variables, the regression coefficients become unstable and their interpretability diminishes. MLR and LR also assume that a high subject-to-variables ratio is present (e.g., >5) and such requirements are not required for PLS. In fact, PLS regression can handle subject-to-variables ratios <1.

3 Results

3.2 Clinical diagnoses and background data

The main causes/diagnoses of pain in the patient group were failed back surgery syndrome with radiculopathy (in one case from cervical level surgery and in another case combined with polyneuropathy) (n = 9), peripheral nerve injury of the lower extremity (n = 3), and peripheral nerve injury of the upper extremity (n = 2). Five patients had concomitant pain syndromes: mild angina pectoris (n = 2), fibromyalgia syndrome (n = 1), tension type headache (n = 1) and polymyalgia rheumatica (n = 1). In the patient group, mean pain duration was 92 ±20 months and mean pain intensity was 67 ± 4 out of 100 on a VASPI scale (Table 1 ). The most frequently used analgesics in the patient group were paracetamol (50%) and opioids (43%). The patients were older than the controls (Table 1). No significant differences in proportion of sex (p = 0.67) or in BMI (p = 0.11) were found between the two groups.

3.2 Basic statistics

Data for IL-1β, IL-6, IL-8, and GM-CSF were available in 14 patients and 17 healthy controls (data of two controls were not included due to analytical failure). Levels of TNF and IL-4 were under the detection limit in all subjects. The plasma level of IL-6 was significantly higher in patients compared to controls (0.92 ± 0.12 pg/ml vs. 0.57 ± 0.08 pg/ml, p = 0.012) (Table 2). For the other three substances (IL-1 β, IL-8, and GM-CSF), levels did not differ significantly between the two groups (Table 2). No significant differences in IL-1 β, IL-6, IL-8, and GM-CSF existed within the pain group between those using opioids and those not using opioids (p: 0.28-0.95).

Table 2

Plasma levels of IL-1β, IL-6, IL-8, and GM-CSF in patients with peripheral chronic neuropathic pain and in healthy controls. Data are presented as mean ± SEM. Furthest to the right is the result of the statistical comparisons between patients and healthy controls.

Patients (n = 14) Controls (n = 17) Statistics (p-value)
IL-1 ß (pg/ml) 0.57 ± 0.10 0.61 ± 0.09 0.625
IL-6 (pg/ml) 0.92 ± 0.12 0.57 ± 0.08 0.012[*]
IL-8 (pg/ml) 3.37 ± 0.22 3.03 ±0.18 0.279
GM-CSF (pg/ml) 0.80 ± 0.08 0.66 ± 0.05 0.200

IL-1β = interleukin 1 beta, I-6 = interleukin 6 (IL-6), IL-8 = interleukin 8, GMCSF = granulocyte macrophage colony-stimulating factor

For all subjects taken together, we found no significant bivariate correlation coefficient (rs) between any of the cytokines (p: 0.13-0.90). However, in the healthy controls, we found a significant bivariate correlation between IL-6 and IL-1β (rs = 0.545, p = 0.024); the other correlations in this group were not significant (p: 0.23-0.92). The corresponding correlation coefficient (rs) between IL-6 and IL-1β in the patient group was -0.08 (p = 0.78). There were no significant bivariate correlations in the patient group (p: 0.06-0.91).

3.3 Multivariate statistics

Regression of group membership: To understand which cytokines best separated between the two groups of subjects, the group membership - patient (denoted 1) vs. controls (denoted 0) - was regressed using the four substances as simultaneous regressors (X-variables). The significant model (R2 = 0.31, Q2=0.24) confirmed that IL-6 was higher in the patient group (VIP= 1.55 (+)) and GM-CSF was borderline significant with a tendency for higher levels in patients (VIP = 0.97 (+)). IL-8 (VIP = 0.78 (+)) and IL-1β (VIP = 0.23 (-)) were not significantly different between these two groups.

Regressions of the levels of IL-6, IL-8, IL-lβ, and GM-CSF: It was not possible to significantly regress the levels of the investigated substances in the controls (using age, sex, and BMI as regressors) or in the patients (using pain intensity, pain duration, using pharmacological treatments, sex, age, and BMI as regressors).

4 Discussion

This systemic (plasma) study of six cyto/chemokines found an elevation of IL-6 in patients with peripheral neuropathic pain compared to healthy controls.

There are some indications suggesting that neuroin-flammation (peripheral and/or central) associated with the chemokine-cytokine network as consequence of nerve damage probably plays an important role in the pathogenesis of neuropathic pain [15,17]. Neuropathic pain pathogenesis involves interactions between neurons, inflammatory immune and immune-like glial cells, as well as inflammatory cytokines and chemokines [2]. This led to the emergence of the notion of neuropathic pain being a neuro-immune disorder, suggesting that the balance between pro- and anti-inflammatory cytokines determines whether chronic neuropathic pain is established or not [2,3,36]. Systemic low-level inflammation is defined as 2-4-fold elevations [25]. We found a twofold elevation of IL-6 (Table 2), a level that indicates low-level inflammation in the present cohort of patients with peripheral neuropathic pain.

The present study confirms other reports concerning plasma/serum IL-6 in human neuropathic pain. In neuropathic pain, due to either herniated intervertebral disc or carpal tunnel syndrome, significantly higher plasma levels of TNF and IL-6 than in healthy controls were found [18,43]. Patients who developed post-herpetic neuralgia had significantly higher levels of IL-6 in serum than those with herpes zoster who did not develop neuralgia; both groups had higher levels of IL-6, IL-1β, TNF, and IL-8 than controls and pain severity in neuralgia correlated positively with IL-6 levels [44]. However, the literature is not univocal. In a study comparing painful and non-painful polyneuropathies, Ludwig et al. did not find significant differences in plasma levels of IL-6 or TNF in serum [21]. Similarly, Backonja et al. did not find elevated IL-6 levels in patients with peripheral neuropathic pain [3]. Normal serum concentrations of IL-1β, IL-6, and TNF were also found in patients with disc herniation and sciatica (this study lacked a control group) [5]. Nonetheless, although IL-6 may actually be anti-nociceptive at the site of injury, the balance of evidence suggests that IL-6 functions as an algesic mediator following nerve injury, not least because it activates spinal cord microglia [2]. Studies in other pain conditions have also reported increases in IL-6. For example, in studies of painful osteoarthritis [22] and fibromyalgia syndrome were found increased levels of IL-6 in blood [29,34].

Studies of biomarkers in different pain conditions do not often take into account confounders such as anti-inflammatory medication, corticosteroids, smoking, inflammatory/autoimmune diseases, infection or obesity [9]. There also reports that opioids may induce neuro-inflammation [41]. However, in the present study no differences in the levels of chemo/cytokines were found between patients using opioids and patients not using opioids. Concerning IL-6, it is important to acknowledge that contracting muscles are the main source of IL-6 in plasma [24]. During exercise, there is a sharp (up to 100-fold) but short increase in plasma concentrations of IL-6 but not in TNF or IL-1β [25,26]. This is not related to muscle damage [25,26]. Importantly, although exercise itself leads to an acute increase in IL-6 production and release by the working muscle, exercise training leads to reduced baseline circulating IL-6 levels [25]. Therefore, in future studies of cytokines and chemokines including IL-6, it will be important to control for exercise habits, and also to consider how recent exercise (i.e., exercise close to the time of drawing blood samples) could confound results. It is generally held that patients with chronic pain have a low physical activity level due to pain per se and/or psychological factors. It seems unlikely that the patients in the present study systematically had been involved in acute exercise to a greater extent than controls prior to drawing blood samples thereby resulting in higher levels of IL-6. If the controls exercised more regularly, their IL-6 levels may have been decreased [25]; that is, the difference between the present two groups would have primarily been due to exercise habits and not the neuropathic pain condition. In addition, the controls were significantly younger, which may indicate both higher activity level and possibly an age effect per se upon IL-6. Concerning the latter, Wilander et al. did not find a significant correlation between different cytokine levels and age [23], and no age effect was seen in the two groups of subjects in our study. Therefore, an age effect per se for plasma IL-6 seems unlikely.

Psychological comorbidities e.g. depressive symptoms are prevalent in chronic pain conditions and are emerging possible confounders. Cytokines (e.g., IL-1β, IL-6, IL-8, and GM-CSF) were increased in depressed patients [8]. In a study comparing patients with and without psychological comorbidities, all subgroups of fibromyalgia had increased levels of TNF, IL-10, and IL-8 compared to controls; there were no subgroup differences [4]. Some reports indicate that depression in psychiatry setting has other characteristics than depression in a pain setting [20]. Hence, more studies are needed in order to understand if psychological comorbidities influence levels of cytokines and chemokines.

Taking the above-mentioned findings into consideration, we propose that it is too early to conclude that neuropathic pain is associated with a systemic IL-6 increase. Moreover, documented studies indicate that IL-6 increase is not specific for neuropathic pain.

Even though plasma is preferred over serum because serum levels are lower for several cytokines [9], it was not possible to detect TNF in plasma with the methodology applied in this study. Other studies of serum and plasma have reported increased levels of TNF in neuropathic pain conditions [10,35]. Fibromyalgia syndrome studies have also found an association with increased TNF [40].

In patients with peripheral neuropathic pain, Backonja et al. found no significant differences concerning IL-1β [3], and the present results are compatible with this observation; however, we found a significant correlation between IL-1β and IL-6 in healthy controls, but not in patients. This finding may be a sign of a disrupted homeostasis, high IL-6 levels leading to loss of correlation between IL-1 β and IL-6 in patients.

We found normal levels of the chemokine IL-8 in plasma. This finding concurs with the results of Backonja et al. in patients with peripheral neuropathic pain [3]. However, patients with painful osteoarthritis have elevated levels of IL-8 in blood [22], and most studies and reviews conclude that fibromyalgia and chronic widespread pain are associated with increased levels of IL-8 in blood [29,30,34,40].

A variety of tumours secrete GM-CSF, which is known to sensitise nociceptors [32]. As there is a mutual interaction between the secretions of TNF and GM-CSF [32] and as TNF is considered to have a pivotal role for both peripheral and central sensitisa-tion in neuropathic pain [19], we investigated whether we could find any evidence for the involvement of GM-CSF in non-cancer, peripheral neuropathic pain; only a tendency to higher values in the multivariate analysis was found.

IL-4 was under the detection limit for all subjects of this study. Hence, a major limitation is that we have results only for pro-inflammatory markers (albeit the above-mentioned complex functions of IL-6). Some studies conclude that chronic pain seems to be associated with lowered anti-inflammatory cytokines such as IL-10 [3,37].

Future studies should analyse the balance between pro-and anti-inflammatory cytokines and also control for possible confounders. Cytokines are a large diverse group of pro- and anti-inflammatory factors produced by several types of cells. Cytokines are not stored as preformed molecules therefore it is difficult to analyse them in plasma. Another important limitation was the relatively low number of subjects in each group due to the fact that this was an additional study prior to a ziconotide trial and the number of patients were calculated with respect to outcomes in the trial. A related limitation was that some patients had concomitant pain conditions. Duration of pain, spreading of pain and medication are possible factors which can affect cytokines in plasma in chronic pain patients.

5 Conclusion

We report here on significantly increased levels of plasma IL-6 in patients with peripheral neuropathic pain. The other investigated pro-inflammatory substances did not differ significantly between groups. However, there are several possible confounders that others and we did not control in this and other similar studies. Notwithstanding, we propose that plasma IL-6 may not be a specific biomarker for neuropathic pain.


DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2015.09.004



Department of Medical and Health Sciences, Faculty of Health Sciences, University of Linköping, SE-581 85 Linköping, Sweden.Tel.: +46 10 103 3661

  1. Conflict of interest The authors declare no conflicts of interest.

Acknowledgements

This study was funded by the Swedish Research Council, the Swedish Council for Working Life and Social Research (2010-0913), the County Council of Östergötland (Sinnescentrum), and the Häl-sofonden Foundation.

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Received: 2015-04-21
Revised: 2015-06-24
Accepted: 2015-06-26
Published Online: 2016-01-01
Published in Print: 2016-01-01

© 2015 Scandinavian Association for the Study of Pain

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