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Central and systemic inflammatory responses to thoracotomy — Potential implications for acute and chronic postsurgical pain
Journal of Neuroimmunology 285 (2015) 147–149
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Central and systemic inflammatory responses to thoracotomy — Potential implications for acute and chronic postsurgical pain Richard M. Talbot a, Kevin F. McCarthy a,b,⁎, Connail McCrory a,b a b
Department of Pain Medicine, St. James's Hospital, Dublin, Ireland Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland
a r t i c l e
i n f o
Article history: Received 7 December 2014 Received in revised form 29 April 2015 Accepted 18 June 2015
Keywords: Chronic postsurgical pain Glia Interleukin Chemokine Cerebrospinal fluid
a b s t r a c t Chronic postsurgical pain (CPSP) may affect up to 70% of patients after surgery. Glial and immune mediators have been implicated in the pathogenesis of chronic postsurgical pain. Our objective was to study cerebrospinal fluid (CSF) and serum concentrations of IL-1β, IL-6, IL-8, IL-10, IFNγ and TNFα over a 72-hour period in patients undergoing a thoracotomy and oesophagectomy. Despite adequate pain control, thoracotomy was still associated with significant central and peripheral inflammation. This must be taken into consideration in planning future strategies to prevent CPSP. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Chronic post-surgical pain (CPSP) is a potentially debilitating complication of elective and emergency surgery that can result in significant physical and economic morbidity for afflicted patients (Van de Ven and Hsia, 2012). The occurrence of CPSP may vary according to the site and type of surgery. Thoracic surgeries have been associated with high rates of CPSP and poorly controlled acute pain has been identified as a risk factor for CPSP after thoracotomy (Katz et al., 1996). Attention has focused on perioperative interventions that might reduce acute pain and the progression to CPSP, among them intrathecal and thoracic epidural analgesia (Andreae and Andreae, 2012; Chaparro et al., 2013). However, currently available analgesic modalities do not offer complete protection from severe acute pain and CPSP. There is compelling pre-clinical evidence for the role of central neuroimmune activation in inflammatory and neuropathic pain (Grace et al., 2014), both of which contribute to CPSP. In the perioperative period, plasma and cerebrospinal fluid (CSF) cytokine levels have not correlated within the first 24 h of major hip and knee surgery (Yeager et al., 1999; Bromander et al., 2012), although these procedures are not associated with high rates of direct nerve trauma. In patients undergoing inguinal hernia repair, where CPSP is typically neuropathic in nature, the systemic administration of a TNFa inhibitor, etanercept, failed to reduce the incidence of CPSP (Cohen et al., 2013). The aim of this study was to assess the changes in, and interactions between, ⁎ Corresponding author at: Department of Pain Medicine, St. James's Hospital, Dublin, Ireland.
http://dx.doi.org/10.1016/j.jneuroim.2015.06.010 0165-5728/© 2015 Elsevier B.V. All rights reserved.
central and peripheral cytokines and acute pain into the third postoperative day after thoracotomy under conditions of optimal postoperative analgesia.
2. Materials and methods 2.1. Subjects and procedures Following institutional ethical approval and written informed consent, we recruited twenty-four patients who were undergoing an oesophagectomy via a thoracotomy under general anaesthesia for the treatment of oesophageal cancer. Exclusion criteria included recent corticosteroid therapy and a history of chronic pain or chronic inflammatory illness. These patients had an intrathecal catheter inserted for the administration of intrathecal morphine for post-operative analgesia in the event of failure or inadequacy of epidural analgesia, which was inserted concurrently. We received consent to take samples of cerebrospinal fluid (CSF) and serum at eight hourly intervals prior to removal of the intrathecal and epidural catheters on the 3rd day after surgery. Pain on coughing or movement (dynamic pain) and pain at rest (static pain) were recorded using an 11-point Numerical Rating Scale (NRS; 0 “no pain” to 10 “worst pain imaginable”) at each sampling time point. Patients received 1 mg of intrathecal morphine at induction of anaesthesia and no other opioids thereafter. Anaesthesia was maintained with isoflurane. Postoperative epidural and parenteral analgesia were titrated to achieve dynamic pain scores of ≤ 7/10 on movement and static pain scores of ≤4/10.
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R.M. Talbot et al. / Journal of Neuroimmunology 285 (2015) 147–149
2.2. Cytokine measurement from CSF and serum samples Prior to induction of general anaesthesia, a 22G spinal catheter (B. Braun Medical Melsungen A/G D/34209) was sited at the L3L4 lumbar interspace. Upon insertion of the catheter and at each sampling interval thereafter, 0.5 mL of CSF was initially withdrawn and discarded to compensate for catheter dead space (0.3 mL) and then a further 1.5 mL of CSF was withdrawn for analysis. Serum samples were taken simultaneously at each time point. CSF and serum were then centrifuged and stored at − 80 °C for subsequent analysis. CSF and serum protein quantification was performed using the MesoScale Discovery (Gaithersburg, MD, USA) human ultra-sensitive assays in accordance with manufacturers' protocols. The limits of detection as reported by the manufacturer were as follows; IFNγ 0.8 pg/mL, TNFα 0.28 pg/mL, IL-1β 0.58 pg/mL, IL-6 0.18 pg/mL, IL-8 0.1 pg/mL, and IL-10 0.57 pg/mL. 2.3. Statistics CSF and serum concentrations of cytokines were tested for a normal distribution and where appropriate log-transformed to permit parametric testing. Changes in CSF and serum cytokine concentrations were assessed with a repeated measures analysis of variance (ANOVA) with a Greenhouse–Geisser estimate of sphericity. Post hoc testing for multiple comparisons across all time points was performed using Dunnett's Multiple Comparison Test and reported a significance of p b 0.05 with correction for multiple comparisons. We tested for relationships between CSF and serum concentrations of cytokines and with static and dynamic pain at each time point using Spearman's rank correlation co-efficient and stepwise multiple linear regression. Correlations between CSF and serum concentrations of each cytokine were assessed with Pearson's product–moment correlation co-efficient (Table 1). Differences in mean concentrations of cytokines between males and females were tested using a Student's t-test. Statistical analysis was performed using GraphPad Prism 6. 3. Results 3.1. Subject characteristics and pain scores The eight women and sixteen men ranged in age from 44 to 84 years (mean 67.3 ± 8.8) and did not have pre-existing pain at the time of surgery. The median duration of anaesthesia was 7.25 h (range 6.5– 8.5 h). Pain scores were highest at the end of surgery (static 2.87 ± 3.0, dynamic 4.87 ± 2.87) and reduced steadily to the end of the study period (static 1.6 ± 1.7, dynamic 2.73 ± 2.32) (Fig. 1). 3.2. Perioperative changes in CSF & serum cytokines There were significant changes in serum concentrations of IL-6 (F = 8.5, p = 0.0011), IL-8 (F = 14.79, p b 0.0001) and IL-10 (F = 5.22, p = 0.0084) throughout the study period. Post hoc testing showed significant elevations in serum IL-1β, IL-6, IL-8, IL-10 and IFNγ at the end of surgery that did not persist beyond 24 h of surgery (Fig. 2). Serum concentrations of TNFα did not change significantly at any point during the study period. The analysis of variance revealed significant changes in CSF concentrations of IL-8 (F = 11.86, p = 0.0009) and TNFα (F = 5.171, p = 0.022). Post hoc comparisons with Dunnett's Multiple Comparison Test revealed a sustained elevation in CSF IL-8 Table 1 Pearson product–moment correlation of serum and CSF cytokines.
Correlation co-efficient p value
TNFα
IL-1β
IL-6
IL-8
IL-10
IFNγ
0.203 0.002
−0.02 0.753
0.091 0.162
0.476 0.00005
0.112 0.083
0.027 0.678
TNFα, Tumour necrosis factor-α; IL, interleukin; IFNγ, interferon-γ.
Fig. 1. Dynamic and static pain scores (mean ± SEM) after thoracotomy, n = 25. Analgesia was titrated to achieve dynamic pain scores of ≤7 and static pain scores ≤4. NRS, 0–10 Numerical Rating Scale.
and transient increases in CSF concentrations of IL-6 and TNFα at individual time points (Fig. 2). There were no significant differences in mean serum or CSF concentrations between males and females. 3.3. Cytokines and pain scores There was a significant inverse correlation between serum concentrations of TNFα and static (r = − 0.209, p = 0.001) and dynamic (r = −0.242, p = 0.0001) pain scores. Dynamic pain scores also correlated positively with serum concentrations of IL-6 (r = 0.178, p = 0.007), IL-8 (r = 0.138, p = 0.033) and IL-1β (r = 0.134, p = 0.038) and inversely with serum concentrations of IFNγ (r = − 0.178, p = 0.006). On stepwise multiple linear regression, only serum TNFα (Beta = − 0.204, t(240) = − 3.68, p = 0.0003) and IL-8 (Beta = 0.015, t(240), p = 0.0005) were retained as variables that were predictive of dynamic pain scores (F(2,237) = 8.89, p b 0.001, R2 = 0.069, R2adjusted = 0.061). CSF and serum concentrations of TNFα (r = 0.203, p = 0.002) and IL-8 (r = 0.476, p = 0.0005) during the study period correlated with each other. 4. Discussion For ethical reasons, each patient received standard care with a combination of epidural and parenteral analgesia that was titrated to their levels of pain. This might uncouple the levels of reported pain from underlying physiological processes. Other potential confounding factors that might exert an effect on the observed concentrations of cytokines are the use of volatile anaesthesia (Wu et al., 2012), the administration of intrathecal morphine (Johnston et al., 2001) and the age of the study participants (Krabbe et al., 2004) and in the perioperative period, other factors such as wound healing and infection may account for an increase in pro- and anti-inflammatory cytokines. Conversely, these conditions are representative of the patient population and clinical management that such patients would currently receive. Even when acute pain is well controlled, as it was in our patients, there is still a significant central neuroimmune response to thoracotomy with changes persisting into the third postoperative day. Our findings may help explain the failure of etanercept, a TNFα inhibitor, to reduce CPSP after hernia surgery when administered subcutaneously prior to surgery (Cohen et al., 2013). Serum concentrations of TNFα did not change significantly throughout the study period and had an inverse relationship with dynamic pain. In addition to this, the predictive power of serum TNFα and IL-8, although significant, only accounted for 6% of the variance in dynamic pain scores. In CSF, while the changes in TNFα and IL-8 were the most significant, neither predicted static or dynamic pain scores. Peripheral blockade of a single cytokine may not be an effective therapeutic strategy to prevent CPSP
R.M. Talbot et al. / Journal of Neuroimmunology 285 (2015) 147–149
149
Fig. 2. Difference in concentrations of cytokines from baseline (mean, 95% confidence interval) throughout study period (repeated measures ANOVA and Dunnett's Multiple Comparison Test, *p b 0.05, **p b 0.01, ***p b 0.001).
as spinal expression of pro-inflammatory mediators such as TNFα, IL-1β and IL-6 may be reciprocal and involve alternative pathways (Schoeniger-Skinner et al., 2007). 5. Conclusions This study demonstrates that there is a substantial central proinflammatory response to thoracotomy despite adequate acute pain control with a combination of intraoperative intrathecal morphine and postoperative epidural analgesia. References Andreae, M.H., Andreae, D.A., 2012. Local anaesthetics and regional anaesthesia for preventing chronic pain after surgery. Cochrane Database Syst. Rev. 10, CD007105. http://dx.doi.org/10.1002/14651858.CD007105.pub2. Bromander, S., Anckarsater, R., Kristiansson, M., Blennow, K., Zetterberg, H., Anckarsater, H., Wass, C.E., 2012. Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study. J. Neuroinflammation 9, 242. http://dx.doi.org/10.1186/1742-2094-9-242. Chaparro, L.E., Smith, S.A., Moore, R.A., 2013. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst. Rev. 7, CD008307. http://dx.doi.org/10.1002/14651858.CD008307.pub2.
Cohen, S.P., Galvagn, S.M., Plunkett, A., Harris, D., Kurihara, C., Turabi, A., Scott Rehrig, S., Buckenmaier, C.C., Chelly, J.E., 2013. A multicenter, randomized, controlled study evaluating preventive etanercept on postoperative pain after inguinal hernia repair. Anesth. Analg. 116, 455–462. http://dx.doi.org/10.1213/ANE.0b013e318273f71c. Grace, P.M., Hutchinson, M.R., Maier, S.F., Watkins, L.R., 2014. Pathological pain and the neuroimmune interface. Nat. Rev. Immunol. 14, 217–231. http://dx.doi.org/10.1038/ nri3621. Johnston, I.N., Milligan, E.D., Wieseler-Frank, J., Frank, M.G., Zapata, V., Campisi, J., Langer, S., Martin, D., Green, P., Fleshner, M., Leinwand, L., Maier, S.F., Watkins, L.R., 2001. J. Neurosci. 24, 7353–7365. Katz, J., Jackson, M., Kavanagh, B.P., Sandler, A.N., 1996. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin. J. Pain 12, 50–55. Krabbe, K.S., Pedersen, M., Bruunsgaard, H., 2004. Inflammatory mediators in the elderly. Exp. Gerontol. 39, 687–699. Schoeniger-Skinner, D.K., Ledeboer, A., Frank, M.G., Milligan, E., Poole, S., Martin, D., Maier, S.F., Watkins, L., 2007. Interleukin-6 mediates low-threshold mechanical allodynia induced by intrathecal HIV-1 envelope glycoprotein gp120. Brain Behav. Immun. 21, 660–667. Van de Ven, T.J., Hsia, H.L.J., 2012. Causes and prevention of chronic postsurgical pain. Curr. Opin. Crit. Care 18, 366–371. http://dx.doi.org/10.1097/MCC.0b013e3283557a7f. Wu, X., Lu, Y., Dong, Y., Zhang, G., Zhang, Y., Xu, Z., Culley, D.J., Crosby, G., Marcantonio, E.R., Tanzi, R.E., Xie, Z., 2012. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-alpha, IL-6, and IL-1beta. Neurobiol. Aging 33, 1364–1378. Yeager, M.P., Lunt, P., Arruda, J., Whalen, K., Rose, R., DeLeo, J.A., 1999. Cerebrospinal fluid cytokine levels after surgery with spinal or general anesthesia. Reg. Anesth. Pain Med. 24, 557–562.
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Central and systemic inflammatory responses to thoracotomy — Potential implications for acute and chronic postsurgical pain Richard M. Talbot a, Kevin F. McCarthy a,b,⁎, Connail McCrory a,b a b
Department of Pain Medicine, St. James's Hospital, Dublin, Ireland Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland
a r t i c l e
i n f o
Article history: Received 7 December 2014 Received in revised form 29 April 2015 Accepted 18 June 2015
Keywords: Chronic postsurgical pain Glia Interleukin Chemokine Cerebrospinal fluid
a b s t r a c t Chronic postsurgical pain (CPSP) may affect up to 70% of patients after surgery. Glial and immune mediators have been implicated in the pathogenesis of chronic postsurgical pain. Our objective was to study cerebrospinal fluid (CSF) and serum concentrations of IL-1β, IL-6, IL-8, IL-10, IFNγ and TNFα over a 72-hour period in patients undergoing a thoracotomy and oesophagectomy. Despite adequate pain control, thoracotomy was still associated with significant central and peripheral inflammation. This must be taken into consideration in planning future strategies to prevent CPSP. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Chronic post-surgical pain (CPSP) is a potentially debilitating complication of elective and emergency surgery that can result in significant physical and economic morbidity for afflicted patients (Van de Ven and Hsia, 2012). The occurrence of CPSP may vary according to the site and type of surgery. Thoracic surgeries have been associated with high rates of CPSP and poorly controlled acute pain has been identified as a risk factor for CPSP after thoracotomy (Katz et al., 1996). Attention has focused on perioperative interventions that might reduce acute pain and the progression to CPSP, among them intrathecal and thoracic epidural analgesia (Andreae and Andreae, 2012; Chaparro et al., 2013). However, currently available analgesic modalities do not offer complete protection from severe acute pain and CPSP. There is compelling pre-clinical evidence for the role of central neuroimmune activation in inflammatory and neuropathic pain (Grace et al., 2014), both of which contribute to CPSP. In the perioperative period, plasma and cerebrospinal fluid (CSF) cytokine levels have not correlated within the first 24 h of major hip and knee surgery (Yeager et al., 1999; Bromander et al., 2012), although these procedures are not associated with high rates of direct nerve trauma. In patients undergoing inguinal hernia repair, where CPSP is typically neuropathic in nature, the systemic administration of a TNFa inhibitor, etanercept, failed to reduce the incidence of CPSP (Cohen et al., 2013). The aim of this study was to assess the changes in, and interactions between, ⁎ Corresponding author at: Department of Pain Medicine, St. James's Hospital, Dublin, Ireland.
http://dx.doi.org/10.1016/j.jneuroim.2015.06.010 0165-5728/© 2015 Elsevier B.V. All rights reserved.
central and peripheral cytokines and acute pain into the third postoperative day after thoracotomy under conditions of optimal postoperative analgesia.
2. Materials and methods 2.1. Subjects and procedures Following institutional ethical approval and written informed consent, we recruited twenty-four patients who were undergoing an oesophagectomy via a thoracotomy under general anaesthesia for the treatment of oesophageal cancer. Exclusion criteria included recent corticosteroid therapy and a history of chronic pain or chronic inflammatory illness. These patients had an intrathecal catheter inserted for the administration of intrathecal morphine for post-operative analgesia in the event of failure or inadequacy of epidural analgesia, which was inserted concurrently. We received consent to take samples of cerebrospinal fluid (CSF) and serum at eight hourly intervals prior to removal of the intrathecal and epidural catheters on the 3rd day after surgery. Pain on coughing or movement (dynamic pain) and pain at rest (static pain) were recorded using an 11-point Numerical Rating Scale (NRS; 0 “no pain” to 10 “worst pain imaginable”) at each sampling time point. Patients received 1 mg of intrathecal morphine at induction of anaesthesia and no other opioids thereafter. Anaesthesia was maintained with isoflurane. Postoperative epidural and parenteral analgesia were titrated to achieve dynamic pain scores of ≤ 7/10 on movement and static pain scores of ≤4/10.
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R.M. Talbot et al. / Journal of Neuroimmunology 285 (2015) 147–149
2.2. Cytokine measurement from CSF and serum samples Prior to induction of general anaesthesia, a 22G spinal catheter (B. Braun Medical Melsungen A/G D/34209) was sited at the L3L4 lumbar interspace. Upon insertion of the catheter and at each sampling interval thereafter, 0.5 mL of CSF was initially withdrawn and discarded to compensate for catheter dead space (0.3 mL) and then a further 1.5 mL of CSF was withdrawn for analysis. Serum samples were taken simultaneously at each time point. CSF and serum were then centrifuged and stored at − 80 °C for subsequent analysis. CSF and serum protein quantification was performed using the MesoScale Discovery (Gaithersburg, MD, USA) human ultra-sensitive assays in accordance with manufacturers' protocols. The limits of detection as reported by the manufacturer were as follows; IFNγ 0.8 pg/mL, TNFα 0.28 pg/mL, IL-1β 0.58 pg/mL, IL-6 0.18 pg/mL, IL-8 0.1 pg/mL, and IL-10 0.57 pg/mL. 2.3. Statistics CSF and serum concentrations of cytokines were tested for a normal distribution and where appropriate log-transformed to permit parametric testing. Changes in CSF and serum cytokine concentrations were assessed with a repeated measures analysis of variance (ANOVA) with a Greenhouse–Geisser estimate of sphericity. Post hoc testing for multiple comparisons across all time points was performed using Dunnett's Multiple Comparison Test and reported a significance of p b 0.05 with correction for multiple comparisons. We tested for relationships between CSF and serum concentrations of cytokines and with static and dynamic pain at each time point using Spearman's rank correlation co-efficient and stepwise multiple linear regression. Correlations between CSF and serum concentrations of each cytokine were assessed with Pearson's product–moment correlation co-efficient (Table 1). Differences in mean concentrations of cytokines between males and females were tested using a Student's t-test. Statistical analysis was performed using GraphPad Prism 6. 3. Results 3.1. Subject characteristics and pain scores The eight women and sixteen men ranged in age from 44 to 84 years (mean 67.3 ± 8.8) and did not have pre-existing pain at the time of surgery. The median duration of anaesthesia was 7.25 h (range 6.5– 8.5 h). Pain scores were highest at the end of surgery (static 2.87 ± 3.0, dynamic 4.87 ± 2.87) and reduced steadily to the end of the study period (static 1.6 ± 1.7, dynamic 2.73 ± 2.32) (Fig. 1). 3.2. Perioperative changes in CSF & serum cytokines There were significant changes in serum concentrations of IL-6 (F = 8.5, p = 0.0011), IL-8 (F = 14.79, p b 0.0001) and IL-10 (F = 5.22, p = 0.0084) throughout the study period. Post hoc testing showed significant elevations in serum IL-1β, IL-6, IL-8, IL-10 and IFNγ at the end of surgery that did not persist beyond 24 h of surgery (Fig. 2). Serum concentrations of TNFα did not change significantly at any point during the study period. The analysis of variance revealed significant changes in CSF concentrations of IL-8 (F = 11.86, p = 0.0009) and TNFα (F = 5.171, p = 0.022). Post hoc comparisons with Dunnett's Multiple Comparison Test revealed a sustained elevation in CSF IL-8 Table 1 Pearson product–moment correlation of serum and CSF cytokines.
Correlation co-efficient p value
TNFα
IL-1β
IL-6
IL-8
IL-10
IFNγ
0.203 0.002
−0.02 0.753
0.091 0.162
0.476 0.00005
0.112 0.083
0.027 0.678
TNFα, Tumour necrosis factor-α; IL, interleukin; IFNγ, interferon-γ.
Fig. 1. Dynamic and static pain scores (mean ± SEM) after thoracotomy, n = 25. Analgesia was titrated to achieve dynamic pain scores of ≤7 and static pain scores ≤4. NRS, 0–10 Numerical Rating Scale.
and transient increases in CSF concentrations of IL-6 and TNFα at individual time points (Fig. 2). There were no significant differences in mean serum or CSF concentrations between males and females. 3.3. Cytokines and pain scores There was a significant inverse correlation between serum concentrations of TNFα and static (r = − 0.209, p = 0.001) and dynamic (r = −0.242, p = 0.0001) pain scores. Dynamic pain scores also correlated positively with serum concentrations of IL-6 (r = 0.178, p = 0.007), IL-8 (r = 0.138, p = 0.033) and IL-1β (r = 0.134, p = 0.038) and inversely with serum concentrations of IFNγ (r = − 0.178, p = 0.006). On stepwise multiple linear regression, only serum TNFα (Beta = − 0.204, t(240) = − 3.68, p = 0.0003) and IL-8 (Beta = 0.015, t(240), p = 0.0005) were retained as variables that were predictive of dynamic pain scores (F(2,237) = 8.89, p b 0.001, R2 = 0.069, R2adjusted = 0.061). CSF and serum concentrations of TNFα (r = 0.203, p = 0.002) and IL-8 (r = 0.476, p = 0.0005) during the study period correlated with each other. 4. Discussion For ethical reasons, each patient received standard care with a combination of epidural and parenteral analgesia that was titrated to their levels of pain. This might uncouple the levels of reported pain from underlying physiological processes. Other potential confounding factors that might exert an effect on the observed concentrations of cytokines are the use of volatile anaesthesia (Wu et al., 2012), the administration of intrathecal morphine (Johnston et al., 2001) and the age of the study participants (Krabbe et al., 2004) and in the perioperative period, other factors such as wound healing and infection may account for an increase in pro- and anti-inflammatory cytokines. Conversely, these conditions are representative of the patient population and clinical management that such patients would currently receive. Even when acute pain is well controlled, as it was in our patients, there is still a significant central neuroimmune response to thoracotomy with changes persisting into the third postoperative day. Our findings may help explain the failure of etanercept, a TNFα inhibitor, to reduce CPSP after hernia surgery when administered subcutaneously prior to surgery (Cohen et al., 2013). Serum concentrations of TNFα did not change significantly throughout the study period and had an inverse relationship with dynamic pain. In addition to this, the predictive power of serum TNFα and IL-8, although significant, only accounted for 6% of the variance in dynamic pain scores. In CSF, while the changes in TNFα and IL-8 were the most significant, neither predicted static or dynamic pain scores. Peripheral blockade of a single cytokine may not be an effective therapeutic strategy to prevent CPSP
R.M. Talbot et al. / Journal of Neuroimmunology 285 (2015) 147–149
149
Fig. 2. Difference in concentrations of cytokines from baseline (mean, 95% confidence interval) throughout study period (repeated measures ANOVA and Dunnett's Multiple Comparison Test, *p b 0.05, **p b 0.01, ***p b 0.001).
as spinal expression of pro-inflammatory mediators such as TNFα, IL-1β and IL-6 may be reciprocal and involve alternative pathways (Schoeniger-Skinner et al., 2007). 5. Conclusions This study demonstrates that there is a substantial central proinflammatory response to thoracotomy despite adequate acute pain control with a combination of intraoperative intrathecal morphine and postoperative epidural analgesia. References Andreae, M.H., Andreae, D.A., 2012. Local anaesthetics and regional anaesthesia for preventing chronic pain after surgery. Cochrane Database Syst. Rev. 10, CD007105. http://dx.doi.org/10.1002/14651858.CD007105.pub2. Bromander, S., Anckarsater, R., Kristiansson, M., Blennow, K., Zetterberg, H., Anckarsater, H., Wass, C.E., 2012. Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study. J. Neuroinflammation 9, 242. http://dx.doi.org/10.1186/1742-2094-9-242. Chaparro, L.E., Smith, S.A., Moore, R.A., 2013. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst. Rev. 7, CD008307. http://dx.doi.org/10.1002/14651858.CD008307.pub2.
Cohen, S.P., Galvagn, S.M., Plunkett, A., Harris, D., Kurihara, C., Turabi, A., Scott Rehrig, S., Buckenmaier, C.C., Chelly, J.E., 2013. A multicenter, randomized, controlled study evaluating preventive etanercept on postoperative pain after inguinal hernia repair. Anesth. Analg. 116, 455–462. http://dx.doi.org/10.1213/ANE.0b013e318273f71c. Grace, P.M., Hutchinson, M.R., Maier, S.F., Watkins, L.R., 2014. Pathological pain and the neuroimmune interface. Nat. Rev. Immunol. 14, 217–231. http://dx.doi.org/10.1038/ nri3621. Johnston, I.N., Milligan, E.D., Wieseler-Frank, J., Frank, M.G., Zapata, V., Campisi, J., Langer, S., Martin, D., Green, P., Fleshner, M., Leinwand, L., Maier, S.F., Watkins, L.R., 2001. J. Neurosci. 24, 7353–7365. Katz, J., Jackson, M., Kavanagh, B.P., Sandler, A.N., 1996. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin. J. Pain 12, 50–55. Krabbe, K.S., Pedersen, M., Bruunsgaard, H., 2004. Inflammatory mediators in the elderly. Exp. Gerontol. 39, 687–699. Schoeniger-Skinner, D.K., Ledeboer, A., Frank, M.G., Milligan, E., Poole, S., Martin, D., Maier, S.F., Watkins, L., 2007. Interleukin-6 mediates low-threshold mechanical allodynia induced by intrathecal HIV-1 envelope glycoprotein gp120. Brain Behav. Immun. 21, 660–667. Van de Ven, T.J., Hsia, H.L.J., 2012. Causes and prevention of chronic postsurgical pain. Curr. Opin. Crit. Care 18, 366–371. http://dx.doi.org/10.1097/MCC.0b013e3283557a7f. Wu, X., Lu, Y., Dong, Y., Zhang, G., Zhang, Y., Xu, Z., Culley, D.J., Crosby, G., Marcantonio, E.R., Tanzi, R.E., Xie, Z., 2012. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-alpha, IL-6, and IL-1beta. Neurobiol. Aging 33, 1364–1378. Yeager, M.P., Lunt, P., Arruda, J., Whalen, K., Rose, R., DeLeo, J.A., 1999. Cerebrospinal fluid cytokine levels after surgery with spinal or general anesthesia. Reg. Anesth. Pain Med. 24, 557–562.