Cerebrospinal Fluid Cytokines and Neurotrophic Factors in Human Chronic Pain Populations: A Comprehensive Review.

REVIEW ARTICLE

Cerebrospinal Fluid Cytokines and Neurotrophic Factors in Human Chronic Pain Populations: A Comprehensive Review Martin F. Bjurstrom, MD*,†; Sarah E. Giron, CRNA‡; Charles A. Griffis, PhD, CRNA† *Cousins Center for Psychoneuroimmunology, University of California, Los Angeles (UCLA), Los Angeles, California ; †Department of Anesthesiology, University of California, Los Angeles (UCLA), Los Angeles, California ; ‡Department of Anesthesiology, University of Southern California (USC), Los Angeles, California U.S.A

& Abstract: Chronic pain is a prevalent and debilitating condition, conveying immense human burden. Suffering is caused not only by painful symptoms, but also through psychopathological and detrimental physical consequences, generating enormous societal costs. The current treatment armamentarium often fails to achieve satisfying pain relief; thus, research directed toward elucidating the complex pathophysiological mechanisms underlying chronic pain syndromes is imperative. Central neuroimmune activation and neuroinflammation have emerged as driving forces in the transition from acute to chronic pain, leading to central sensitization and decreased opioid efficacy, through processes in which glia have been highlighted as key contributors. Under normal conditions, glia exert a protective role, but in different pathological states, a deleterious role is evident—directly and indirectly modulating and enhancing pain transmission properties of neurons, and shaping synaptic plasticity in a dysfunctional manner. Cytokines and neurotrophic factors have been identified as pivotal mediators involved in neuroimmune activation pathways and

Address correspondence and reprint requests to: Martin F. Bjurstrom, MD, Cousins Center for Psychoneuroimmunology, UCLA, 300 UCLA Medical Plaza, Suite 3132, Los Angeles, CA 90095-7076, U.S.A. E-mail: [email protected]. Submitted: June 3, 2014; Revision accepted: September 15, 2014 DOI. 10.1111/papr.12252

© 2014 World Institute of Pain, 1530-7085/16/$15.00 Pain Practice, Volume 16, Issue 2, 2016 183–203

cascades in various preclinical chronic pain models. Research confirming these findings in humans has so far been scarce, but this comprehensive review provides coherent data supporting the clear association of a mechanistic role of altered central cytokines and neurotrophic factors in a number of chronic pain states despite varying etiologies. Given the importance of these factors in neuropathic and inflammatory chronic pain states, prospective therapeutic strategies, and directions for future research in this emerging field, are outlined. & Key Words: chronic pain, neuroimmune activation, cytokines, neurotrophic factors, neuroinflammation, cerebrospinal fluid, review

INTRODUCTION Chronic pain is a dreaded condition, affecting about one-third of the adult population in the United States and Europe.1–4 Among patients with cancer, pain is considered the most important symptom to alleviate, and the prevalence of pain for those with metastatic or terminal disease has been estimated to 64%.5 Chronic postsurgical pain (CPSP) is a phenomenon afflicting 10% to 50% of patients undergoing common procedures, and even minor procedures are associated with substantial pain-related morbidity.6,7 Inadequate, unsatisfactory treatment of chronic pain is common, not the

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least among elderly, in hospital geriatric departments, and around half of cancer pain patients are undertreated.8,9 The prevalence of neuropathic pain in the general population has been estimated to range between 1% and 17.9%,10 but higher figures are observed among those referred to tertiary care pain clinics, constituting a more complex group to treat.11,12 Suffering from chronic pain is not only caused by painful symptomatology, but also through a wide range of psychopathological and physical consequences, including depression and anxiety disorders, impaired sleep and cognition, cardiovascular morbidity and impaired sexual function, all contributing to diminished quality of life.13 The human burden thus is immense, conveying enormous societal costs, amounting to about 3% to 10% of GDP in European countries,14,15 and $560 to 635 billion in direct and indirect costs in the United States.16 Distinct chronic pain conditions, especially those with neuropathic features, are especially refractory to the currently available armamentarium of psychological, physical, complementary, pharmacological, and interventional treatments. Despite specialized state-of-the-art multimodal treatment, results are too often futile and deteriorating pain lingers. Aggressive pain treatment is also commonly associated with side effects and risk for adverse events, which further limits the success of pain relief. There is clearly a need for more effective and targeted therapeutics, and further elucidation of the complex pathophysiological mechanisms underlying chronic pain conditions, to better alleviate pain more profoundly than today. A large body of preclinical evidence implicates proinflammatory cytokines and neurotrophic factors in the induction and maintenance of inflammatory and neuropathic chronic pain states. Data obtained in neuropathic pain models show elevated levels of proinflammatory cytokines and neurotrophic factors at multiple levels of the nervous system, including peripheral nerve, dorsal root ganglia, spinal cord, and brain. Antagonism of these factors have shown beneficial effects on pain behavior and hyperalgesia, implicating a strong role in the underlying pathogenic mechanisms.17–19 Central neuroimmune activation and neuroinflammation are driving forces in the transition from acute to chronic pain, leading to central sensitization20 and decreased opioid efficacy,21 and glia, particularly microglia, have been highlighted as key contributors.17,22,23 Under normal conditions, glia exert a protective, defensive role, acting as “guardians” and “electricians” of the central nervous

system (CNS), but in different pathological states, a deleterious role is evident—directly and indirectly modulating and enhancing pain transmission properties of neurons, and shaping synaptic plasticity in a dysfunctional manner.18,24,25 In various preclinical chronic pain models, cytokines and neurotrophic factors have been identified as pivotal mediators involved in neuroimmune activation pathways and cascades, and in neuron–glia interactions.17,19,24,26,27 Research confirming these findings in humans has so far been scarce and never evaluated in a comprehensive manner. In this study, we review all currently available publications on cerebrospinal fluid (CSF) cytokines and neurotrophic factors in human chronic pain populations, outline prospective therapeutic strategies, and suggest directions for future research in this emerging field.

METHODS A literature search was conducted using the PubMed search engine, Cochrane databases, and a manual search of all identified pertinent references, through May 2014. In this study, chronic pain was defined according to the criteria of the International Association for the Study of Pain (IASP), temporally exceeding normal tissue healing time (usually considered 3 months) and not bearing any apparent biological value.28 Keywords employed in the search process were cytokine(s), interleukin(s), neurotrophic factor(s), neurotrophin(s), cerebrospinal fluid (CSF), neuropathic, inflammatory, central, inflammation, chronic, pain, immune, glial, markers, in various combinations. Relevant ongoing trials were searched using national and international trials registers. The language of publications and trials was not an exclusion criterion. Cytokines in Creation and Maintenance of Chronic Pain States Cytokines are small polypeptides, released by neurons, activated microglia and astrocytes, monocytes, macrophages and T cells, spanning a myriad of immune and physiologic functions.29–31 A vast number of cytokines have been discovered, and several subdivisions based on different properties exist.32 Although cytokines are known to play a role in peripheral neuroimmune interactions, this study focuses on the effects of cytokines in the central compartment (spinal cord and brain). Acting as mediators in the cross talk between glia

Chronic Pain, Central Cytokines, and Neurotrophic Factors 187

tion.66 Glutamate itself can also stimulate BDNF release, creating a vicious positive feedback loop. Glial Cell Line-Derived Neurotrophic Factor (GDNF). GDNF supports survival of various subpopulations of neurons, exerts protective and regenerative effects, and has due to its relatively high specificity for dopaminergic neurons been examined in clinical studies in Parkinson’s disease. Intraputamenal GDNF infusion has, however, so far shown weak results, and adverse events have caused discontinuation of this potential therapy.26,68,73 GDNF is produced by neurons in the peripheral nervous system (PNS) and CNS, by astrocytes, in peripheral tissues, and in joint inflammation by chondrocytes. The exact mode of action has not yet been established, as contradictory results in different models exist, and both pro- and analgesic effects have been observed.73 GDNF is, however, generally considered neuroprotective, anti-inflammatory, and pain attenuating.68,75,76 It activates the tyrosine kinase receptor Ret– glycosylphosphatidylinositol–coreceptor a (GFR a) complex, triggering signaling cascades and not fully understood downstream effects.73 Central Cytokines and Neurotrophic Factors in Chronic Pain—Studies in Human Populations While there is a solid body of preclinical evidence on central cytokines and neurotrophic factors contributing to pathophysiological mechanisms underlying chronic pain, research in humans has so far been limited. Considering this scarcity, all studies published to date (Table 1), even with apparent methodological flaws, are reviewed below, grouped after chronic pain entity. Osteoarthritis (OA). Pain is the primary symptom of OA, which is the most common form of arthritis, and among the top 10 causes of disability worldwide.77 The prevalence of OA increases with age; in older adults in the United States, lower extremity OA is the leading cause of mobility impairment.77 The hallmarks of OA pathology are degradation and remodeling of joint tissues. Typically, the pain consists of an activity-related mechanical component, relieved by rest; with time, a more persistent background pain develops. Although evidence for specific nerve lesions in OA is lacking, neuropathic features are reported by about one-third of knee OA patients.77 OA pain is generated and maintained through peripheral nociceptive input from the joint, but central sensitization is also a contributing

factor.69,78 The correlation between structural joint changes (radiographic severity of OA) and pain has in several studies been poor, and the fact that 10% to 20% of knee OA patients still suffer persistent severe knee pain after total knee replacement highlights the role of central mechanisms maintaining the pain.69,78 Lundborg et al.79 examined patients with chronic pain about to undergo arthroplastic surgery due to knee or hip OA (n = 20). CSF was obtained through lumbar puncture prior to delivery of spinal anesthesia, and IL1b, IL-6, IL-8, IL-10, TNF-a, and GDNF were measured in CSF and blood. Compared to controls, the OA patients showed the following statistically significant findings: higher GDNF in CSF, lower GDNF in blood, higher IL-8 in both CSF and blood, higher IL-1b in CSF, and higher IL-6 in blood. In both the OA and the control group levels of GDNF were higher in blood compared to CSF. No significant correlations between intensity or duration of pain and levels of GDNF were found. Buvanendran et al.80 conducted a randomized, double-blinded study on hip OA patients undergoing arthroplastic surgery (n = 30), receiving either the oral cyclooxygenase 2 (COX-2) inhibitor rofecoxib or placebo in the preoperative period. Before administration of spinal anesthesia, samples of CSF were collected, and an IT catheter was left in place for 30 hours after surgery, permitting repeated sampling of CSF for the purpose of examining surgery-induced inflammatory response. IL-1b, IL-6, IL-8, and TNF-a were analyzed in CSF and blood, and unfortunately no pain-free control group existed. CSF IL-1b and TNF-a were undetectable, and concentrations of IL-6 and IL-8 were only provided in relation to the baseline values, as slopes. The main conclusions, regarding central cytokines and mediators derived from this study, were that arthroplastic hip surgery was associated with postoperative upregulation of IL-6, IL-8, and prostaglandin E2 (PGE2), and that the COX-2 inhibitor reduced PGE2 and IL-6. In a controlled study on patients undergoing hip arthroplasty (n = 19), Yeager et al.81 focused on changes in cytokine levels associated with different types of anesthesia. CSF and blood levels of IL-6 and IL-10 were measured pre- and postoperative, and several important data related to chronic pain were unfortunately not provided. Although exact baseline levels of IL-6 and IL-10 were not described, the authors stated that the controls and patients all had low or undetectable levels of these markers in both CSF and blood, with no significant differences.

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Neurotrophic Factors in Creation and Maintenance of Chronic Pain States Neurotrophic factors are crucial for neuronal growth and survival during development and in the adult nervous system for maintenance and regenerative processes, for example, after peripheral axon damage or central nervous system injuries.66 Most interest has been devoted to the neurotrophin (NT) superfamily [NGF, BDNF, neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5)] and the glial cell line-derived neurotrophic factor (GDNF)-related family (GDNF, neurturin, persephin, and artemin). These factors have been highlighted not only in chronic pain states, but also in neurodegenerative conditions, depression, and schizophrenia, where low levels have been observed, and preclinical and clinical trials utilizing replacement strategies show promise for some neurodegenerative disorders.67,68 Several of the neuroplastic and neurochemical changes that occur in various chronic pain states are regulated by neurotrophic factors, and pivotal roles have been identified for NGF, BDNF, and GDNF. Nerve Growth Factor (NGF). NGF is produced in a number of different cell types, such as in skin basal keratinocytes and visceral epithelial cells, but inflammation can trigger, for example, mast cells, macrophages, and Schwann cells to express NGF.66 In osteoarthritis, NGF can be produced by articular cartilage and synovium.69 The crucial role of NGF and its receptor tyrosine kinase A (TrkA) is apparent by the fact that genetic mutation in, or loss of, any of the two causes detrimental or dramatic effects. Mice lacking NGF or TrkA typically die within 1 month after birth and display severe sensory and sympathetic neuropathies, while mutation in TrkA (hereditary sensory autonomic neuropathy (HSAN) IV) or NGF (HSAN V) causes congenital partial or complete insensitivity to pain perception.70 Upon peripheral release, NGF serves as an algogenic inflammatory mediator, but NGF is also an indirect central pain modulator via endocytosis at the distal nerve terminal and retrograde transport to the sensory neuron soma in the dorsal root ganglion (DRG), where it regulates gene expression. The central effect is directly shown through IT administration of NGF, which produces pain and evokes thermal hyperalgesia.71,72 The effect of NGF is mediated through binding of a receptor complex, TrkA receptor/p75 neurotrophin receptor (p75NTR), which activates signaling pathways culminating in upregulation of sensory neuropeptides

(SP, calcitonin gene-related peptide (CGRP)), BDNF, ligand-gated ion channels (transient receptor potential vanilloid (TRPV) 1, purinergic ATP receptor, and bradykinin B2 receptor) and voltage-gated ion channels (Nav 1.3, Nav 1.8, and Nav 1.9).26,66,70,73 Nongeneregulatory effects are also mediated through NGF-TrkA interaction activating phospholipase C, directly sensitizing TRPV1.70,73 All of these NGF-evoked changes activate and sensitize nociceptive neurons directly, and indirectly through activation of mast cells, neutrophils and sympathetic efferent neurons. Interestingly, after injury to peripheral sensory axons, Schwann cells distal to the site of injury, and satellite cells in the DRG, unsuccessfully increase expression of neurotrophic factors to try to compensate the loss of trophic factors due to interrupted retrograde transport.26 When injury fails to transect the entire nerve fascicule, the remaining intact fibers compete with fewer others for trophic factors. Some of the features of neuropathic pain are likely accounted for by increased trophic factors to spared afferents, and by the disturbed BSCB.26 Brain-Derived Neurotrophic Factor (BDNF). BDNF is synthesized by some DRG neurons, microglia, and astrocytes. It is upregulated in inflammatory pain conditions,66 neuropathic pain,27,74 and functions as a central modulator of pain. Additionally, peripheral effects of BDNF seem to be important, as chronic pancreatitis exhibits high pancreatic levels of BDNF which have been found to correlate with pain intensity.66 NGF upregulates BDNF through actions mediated by TrkA activation, but BDNF upregulation is also driven by microglia. Activation of microglia upregulates, among other factors, a purinergic ATP-binding receptor (P2X4R) which upon activation causes Ca2+ influx, further activating intracellular signaling cascades, resulting in increased expression and release of BDNF.18,19 BDNF in turn binds the postsynaptic tyrosine kinase B (TrkB) receptor, causing downregulation of K+-Cl cotransporter 2 (KCC2) expression which reduces neuronal Cl extrusion capacity and thus weakens GABA/ Glycine-mediated inhibition, which ultimately results in increased neuronal firing.18,19,27 This chain of events is referred to as the P2X4R-BDNF-TrkB-KCC2 cascade and has in animal models been proved critical to the generation and maintenance of neuropathic pain states,18,19 and opioid-induced hyperalgesia (OIH).18 BDNF has also been found to increase glutamatergic neurotransmission through phosphorylation of NMDA receptors, which are key players in central sensitiza-


the CSF of patients with Complex Regional Pain Syndrome. Brain Behav Immun. 2007;21:668–676. 89. Munts AG, Zijlstra FJ, Nibbering PH, et al. Analysis of cerebrospinal fluid inflammatory mediators in chronic complex regional pain syndrome related dystonia. Clin J Pain. 2008;24:30–34. 90. Backonja MM, Coe CL, Muller DA, Schell K. Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients. J Neuroimmunol. 2008;195:157–163. 91. Yawn BP, Gilden D. The global epidemiology of herpes zoster. Neurology. 2013;81:928–930. 92. Philip A, Thakur R. Post herpetic neuralgia. J Palliat Med. 2011;14:765–773. 93. Watson CP, Morshead C, Van der Kooy D, Deck J, Evans RJ. Post-herpetic neuralgia: post-mortem analysis of a case. Pain. 1988;34:129–138. 94. Watson CP, Deck JH, Morshead C, Van der Kooy D, Evans RJ. Post-herpetic neuralgia: further post-mortem studies of cases with and without pain. Pain. 1991;44:105–117. 95. Kikuchi A, Kotani N, Sato T, et al. Comparative therapeutic evaluation of intrathecal versus epidural methylprednisolone for long-term analgesia in patients with intractable postherpetic neuralgia. Reg Anesth Pain Med. 1999;24:287–293. 96. Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med. 2000;343:1514–1519. 97. Nelson DA, Landau WM. Intrathecal methylprednisolone for postherpetic neuralgia. N Engl J Med. 2001;344:1019; author reply 1021–1012. 98. Niebergall H, Priebe HJ. Intrathecal methylprednisolone for postherpetic neuralgia. N Engl J Med. 2001;344:1020; author reply 1021–1022. 99. Lewis G. Intrathecal methylprednisolone for postherpetic neuralgia. N Engl J Med. 2001;344:1020; author reply 1021–1022. 100. Lampe JB, Hindinger C, Reichmann H. Intrathecal methylprednisolone for postherpetic neuralgia. N Engl J Med. 2001;344:1019–1020; author reply 1021–1012. 101. Srinivasan B. Intrathecal methylprednisolone for postherpetic neuralgia. N Engl J Med. 2001;344:1021; author reply 1021–1022. 102. Zetlaoui PJ, Cosserat J. Intrathecal methylprednisolone for postherpetic neuralgia. N Engl J Med. 2001;344:1020–1021; author reply 1021–1022. 103. Rijsdijk M, van Wijck AJ, Meulenhoff PC, et al. No beneficial effect of intrathecal methylprednisolone acetate in postherpetic neuralgia patients. Eur J Pain. 2013;17:714– 723. 104. Kotani N, Kudo R, Sakurai Y, et al. Cerebrospinal fluid interleukin 8 concentrations and the subsequent development of postherpetic neuralgia. Am J Med. 2004;116:318– 324. 105. Rijsdijk M, van Wijck AJ, Kalkman CJ, et al. Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs. Anesthesiology. 2012;116:170–181.

106. Queiroz LP. Worldwide epidemiology of fibromyalgia. Curr Pain Headache Rep. 2013;17:356. 107. Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010;62:600–610. 108. Larson AA, Giovengo SL, Russell IJ, Michalek JE. Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain. 2000;87:201–211. 109. Uceyler N, Hauser W, Sommer C. Systematic review with meta-analysis: cytokines in fibromyalgia syndrome. BMC Musculoskelet Disord. 2011;12:245. 110. Giovengo SL, Russell IJ, Larson AA. Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol. 1999;26:1564– 1569. 111. Kadetoff D, Lampa J, Westman M, Andersson M, Kosek E. Evidence of central inflammation in fibromyalgiaincreased cerebrospinal fluid interleukin-8 levels. J Neuroimmunol. 2012;242:33–38. 112. Li Y, Xiao B, Qiu W, et al. Altered expression of CD4 (+)CD25(+) regulatory T cells and its 5-HT(1a) receptor in patients with major depression disorder. J Affect Disord. 2010;124:68–75. 113. Kim YK, Na KS, Shin KH, et al. Cytokine imbalance in the pathophysiology of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1044–1053. 114. Sarchielli P, Alberti A, Candeliere A, et al. Glial cell line-derived neurotrophic factor and somatostatin levels in cerebrospinal fluid of patients affected by chronic migraine and fibromyalgia. Cephalalgia. 2006;26:409–415. 115. Sarchielli P, Mancini ML, Floridi A, et al. Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome. J Pain. 2007;8:737–745. 116. Bjersing JL, Dehlin M, Erlandsson M, Bokarewa MI, Mannerkorpi K. Changes in pain and insulin-like growth factor 1 in fibromyalgia during exercise: the involvement of cerebrospinal inflammatory factors and neuropeptides. Arthritis Res Ther. 2012;14:R162. 117. Taylor RS, Taylor RJ. The economics of failed back surgery syndrome. Br J Pain. 2012;6:140–141. 118. Bokov A, Isrelov A, Skorodumov A, et al. An analysis of reasons for failed back surgery syndrome and partial results after different types of surgical lumbar nerve root decompression. Pain Physician. 2011;14:545–557. € et al. Axon count 119. Tilki HE, Cosßkun M, Akdemir NU, and sympathetic skin responses in lumbosacral radiculopathy. J Clin Neurol. 2014;10:10–16. 120. McCarthy KF, Connor TJ, McCrory C. Cerebrospinal fluid levels of vascular endothelial growth factor correlate with reported pain and are reduced by spinal cord stimulation in patients with failed back surgery syndrome. Neuromodulation. 2013;16:519–522.

Year

2010

2006

1999

2007

2005

2008

2008

1999

2000

Ref #

79

80

81

88

87

90

89

95

96

PHN

PHN

CRPS (+dystonia)

PTN (CRPSI/II); DPPN

CRPS

CRPS

Hip OA

Hip OA

Knee OA

Pain Population

270

25

20

8;6

24

22

19

30

20

N

138:132

11:14

0:20

3:5;5:1

3:21

5:17

NI

19:11

9:11

M:F

64

65

42

42

40

45.5

NI

69.8

68.1

Age

Healthy

None

Pain-free spinal anesthesia pts

Healthy

RP, SPL, PN, SFN, NPH w shunt pts

RP, ALS, PN, SPL, NPH pts

Healthy

None

Pain-free spinal anesthesia pts

Controls

3.2 (NI)/6.7

10.0 (2.0 to 20.0)/ 8.0 2.2 (NI)/6.1

10.1 (0.8 to 20.2)/ NI

7 (0.5 to 27)/7.5

8.4 (0.5 to 31)/7.2

NI/NI

NI/NI

3.6 (0.5 to 15)/8.5

Pain Duration (years)/Severity (VAS)

IL-8

IL-1b, IL-6, IL-8, IL-10, IL-12, TNF-a (sTNFr, IL-1ra) IL-1b, IL-6, IP-10, RANTES IL-1b, IL-6, IL-8, TNF-a

IL-1b, IL-6, TNF-a

IL-4,Il-6, IL-8, IL-10

IL-6, IL-10

IL-1b, IL-6, IL-8, TNF-a

IL-1b, IL-6, IL-8, IL-10, TNF-a

CSF Cytokines

None

None

IL-1b, IL-6, IL-8, IL-10, IL-12, TNF-a (sTNFr, IL-1ra) None

None

None

None

None

None

None

None

None

NPQ, NPS, BPI-sf

None

None

None

None

None

None

Sleep disturbance (0 to 10)

None

IL-1b, IL-6, IL-8, TNF-a

None

SF-36

GDNF*

IL-1b, IL-6, IL-8, IL-10, TNF-a

IL-6, IL-10

Q’naires/ Scales

CSF Neurotrophic Factors

Blood Cytokines

Table 1. Studies Examining CSF Cytokines and Neurotrophic Factors in Human Chronic Pain Populations

CSF: IL-8↑ (compared to reference values). IL-1b, IL6, TNF-a ND. IL-8 decreased sig in the IT treatment group. Sig & greater improvement of pain in the IT MEP vs. ED MEP group up to 24 weeks FU. CSF: IL-8↑. IL-8 prerandomization inversely correlated with duration

CSF: GDNF↑, IL-1b↑, IL-8↑. Blood: GDNF↓, IL-6↑. *the only study measuring a neurotrophic factor (GDNF) also in blood CSF: IL-1b, TNF-a ND. Initially postop IL-6↑. Preop COX2-inhibitor ? CSF PGE2↓, IL-6↓. CSF PGE2 pos correlation w postop pain; CSF IL-6 pos correlation w sleep disturbance CSF/blood: low/ND levels of IL-6, IL-10 in all groups. No sig. differences CSF: IL-6↑, IL-4↓ (when samples falling below sensitivity of ELISA removed), IL-10↓ (CRPS, RP, SPL groups). CRPS - highest average level of glutamate. IL-8 no sig differences & no correlation pain levels CSF: IL-1b↑, IL-6↑; non-sig tendency IL-6↑ correlating to VAS pain scores↑. IL-1b ND in many individuals. CSF: IL-1b↑, sTNFr↑ Blood: sTNFr↑; CSF/Blood ratio IL8↑; IL-10↓ (blood, CSF) pain↑; IL-1b↑, IL-1ra↑ (CSF) -pain↑ No sig results.

Results

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Year

2013

1999

2011

2007

2006

2012

2013

2010

Ref #

103

110

111

115

114

116

120

121

Mixed (CLBP, FBSS, CNP, OA etc)

FBSS

FM

CM, PCM, PAAH, FM

FM, CM

FM

FM, SFM, mixed

PHN

Pain Population

Table 1. (Continued)

6:3

25:35

60

0:49

11:40

7:33

NI

10:49

4:6

M:F

9

49

51

40

15

59

10

N

56

47

52

41

39.2

46.2

45.8

73.6

Age

None

Matched chronic LBP pts (0 FBSS, 0 SCS)

None

Same type of controls as ref # 115

Diagnostic LP pts, 0 CNS/0 systemic disease, age-matched, 0 meds > 2 months

Headache pts (0 infl disease, 0 meds)

Healthy

None

Controls

NI/5.3;5.7

NI/3.9

11.0 (NI)/7.1

11.3 (NI)/7.5

12.3 (NI); 11.4 (NI)/ 7.8;8.0

10.3 (2 to 30)/6.6

NI/NI

1.9 (0.8 to 7.3)/ 7.2


IL-6, IL-10

MCP-1

IL-6, IL-8

None

None

IL-1b, IL-8

None

IL-1a, IL-1b, IL-6, IL-8, IL-10, TNF-a, MCP-1, fractalkine None

IL-6, IL-10

None

None

None

None

IL-1b, IL-5, IL-6, IL-8, IL-10, TNF-a

None

Blood Cytokines

CSF Cytokines

None

BDNF, VEGF

NGF

GDNF

BDNF, NGF

None

NGF

None


None

SF-36, BPI

FIQ

None

HADS, MFI-20, PSQI, SF-36, FIQ BPI-sf, MIDAS, HIT-6, FIQ, HRQoL, SF-36, SCL-90

TTPpal, TPI, APT

EQ5D

Q’naires/ Scales

CSF: BDNF↑, NGF↑, glutamate↑ (FM, CM). Sig pos correlation between BDNF, NGF & glutamate. BDNF, NGF sig correlated w duration of chronic pain, but not w pain intensity/BPI-sf/FIQ-scores. CSF: GDNF↓, somatostatin↓ (for all groups compared to controls); sig pos correlation GDNF – somatostatin. CSF: BL IL-6 correlated pos w SP & inversely w NGF. CSF: BDNF↑, MCP-1↑. BDNF, VEGF pos correlations w reported pain. After 5 minute SCS - VEGF↓. CSF: IL-6↑. Long-term IT MO/HM group: sig inverse correlation pain score – plasma IL-6, IL-10; CSF IL-6 5x↑ relative to pts receiving IT MO/HM 3 months. No sig correlation pain – CSF cytokines. De novo IT treatment group: IL-6↑ 3x

CSF: NGF↑ (primary FM group), SP↑ in all three pain groups CSF: IL-8↑. Blood: IL-8↑, IL1b↓, IL-5↓, TNF-a↓.

of PHN. IL-8 unchanged in control and Ld-only group over 2 year FU. IL-8↓ by 50% during MEP-Ld treatment – correlated with pain relief. CSF: IL-8↑ & MCP-1↓ after MEP-Ld treatment. IL-1a, IL-1b, IL-10, TNF-a, MIP-1a, fractalkine ND in > 70% of samples.

Results


2009

2011

2002

2009

2002

2001

2007

2008

122

123

124

126

130

129

131

132

PNP (painful/ non-painful)

NDPH, CM, PTH

CDH

CNP (postop) /CLBP CDH

Sciatica

Lumbar RP

Lumbar RP

36

38

20

25

10; 20

39

30

19

N

22:14

6:32

5:15

7:18

5:5; 7:13

26:13

NI

15:4

M:F

64.3

32.3

43.6

46.5

63.3

39

63

53.5

Age

None

CM, PTH

Same type of controls as ref # 115

Healthy, admitted for LP (0 CNS/ systemic disease)

CLBP, NPH

Spinal anesthesia pts (removal of devices after osteosynthesis) FU arthroscopic knee pts (0 pain, 0 spinal disorders) None (results compared to reference values)

Controls

NI/NI

4.0 (0.3 to 31)/NI

12.3 (NI)/7.5

1.9 (0.7 to 4.1)/8.0;NI 23.1 (NI)/7.4

IL-6, TNF-a

TNF-a

None

None

None

IL-1b, IL-6, IL-8, IFN-c, TNF-a

IL-6, TNF-a

> 0.5/3.2; 5.4 (back; leg)

0.5 (0.01 to 3.0)/4.3

IL-1b, IL-6, TNF-a

CSF Cytokines

3.9 (0.2 to 10)/NI


IL-6, TNF-a

TNF-a

None

None

None

IL-1b, IL-6, IL-8, IFN-c, TNF-a

None

None

Blood Cytokines

None

None

NGF

GDNF, BDNF, CNTF, NGF BDNF, NGF

None

None

None


PNP severity score

None

None

None

None

None

None

JOA low back pain-score

Q’naires/ Scales

CSF: BDNF↑, NGF↑, glutamate↑. Sig pos correlation between BDNF-NGF-glutamate in CDH pts. Sig pos correlation between NGF -duration CDH. CSF: NGF↑, CGRP↑, SP↑. Sig pos correlation NGF/SP/ CGRP – duration CDH & headache frequency. CSF: TNF-a↑ in pts & controls. Blood: TNF-a normal levels in most subjects. CSF/blood: no sig differences in IL-6, TNF-a between groups. Pts w mechanical allodynia – blood TNF-a↑. More severe PNP – blood IL-6↑, TNF-a↑.

CSF: IL-6↑. TNF-a ND. Sig correlation IL-6 - severity of dural space restriction at the compression site. CSF: IL-8↑ in 12/39 pts positive correlation w short duration sciatic pain & more pronounced herniation. CSF/blood: normal levels of IL-1b, IL-6, IFN-c, TNF-a. No sig results.

by 3 months, CSF IL-10 unchanged. CSF: IL-6↑. IL-1b, TNF-a ND.

Results

Treatment modalities: COX2, Cyclooxygenase 2; ED, Epidural; HM, Hydromorphone; IT, Intrathecal; Ld, Lidocaine; MEP, Methylprednisolone; MO, Morphine; SCS, Spinal Cord Stimulation. Pain population: CDH, Chronic Daily Headache; CLBP, Chronic LBP; CM, Chronic Migraine; CNP, Chronic Neuropathic Pain; CRPS, Complex Regional Pain Syndrome; DPPN, Distal Painful non-diabetic Polyneuropathy; FBSS, Failed Back Surgery Syndrome; (S)FM, (Secondary) Fibromyalgia; LBP, Low Back Pain; NDPH, New Daily Persistent Headache; OA, Osteoarthritis; PAAH, Probable Analgesic-Abuse Headache; PCM, Probable Chronic Migraine; PHN, Postherpetic Neuralgia; PNP, Polyneuropathy; PTH, Post-traumatic Headache; PTN, Post-traumatic Neuralgia; RP, Radiculopathy. Conditions: ALS, Amyotrophic Lateral Sclerosis; NPH, Normal Pressure Hydrocephalus; PN, Peripheral Neuropathy; RP, Radiculopathy; SFN, Small Fiber Neuropathy; SPL, Spondylolisthesis. Questionnaires: APT, average pain threshold; BPI (-sf), Brief Pain Inventory (-short form); FIQ, Fibromyalgia Impact Questionnaire; HADS, Hospital Depression and Anxiety Scale; HIT-6, Headache Impact Test; HRQoL, Health-Related Quality of Life; JOA, Japanese Orthopaedic Association; MFI-20, Multidimensional Fatigue Inventory; MIDAS, Migraine Disability Assessment Questionnaire; NPQ, Neuropathic Pain Questionnaire; NPS, Neuropathic Pain Scale; PSQI, Pittsburgh Sleep Quality Index; SCL-90, Symptom Check List; SF-36, Short Form-36; TPI, tender point index; TTPpal, total tender points palpation; VAS, Visual Analogue Scale. CSF/blood markers: BDNF, Brain-Derived Neurotrophic Factor; CGRP, Calcitonin-Gene-Related Peptide; CNTF, Ciliary Neurotrophic Factor; GDNF, Glial cell line-Derived Neurotrophic Factor; IL, Interleukin; IP-10, Interferon-c inducible Protein-10; MCP-1, Monocyte Chemotactic Protein-1; NGF, Nerve Growth Factor; PGE2, Prostaglandin E2; RANTES, Regulated upon Activation, Normal T-cell Expressed and Secreted; SP, Substance P; VEGF, Vascular Endothelial Growth Factor. Miscellaneous: BL, Baseline; CNS, Central Nervous System; conc, concentration; FU, Follow-up; LP, Lumbar Puncture; ND, Non-detectable; NI, Not Implemented; pos, positive; pt(s), patient(s); sig, significant; sxs, symptoms; w, with.

Year

Ref #

Pain Population

Table 1. (Continued)

190 BJURSTROM ET AL.


The finding of elevated central levels of GDNF would be in line with a proanalgesic effect of this factor, but the exact role and mechanism of GDNF remains to be determined. No correlation between GDNF, or cytokine levels, and pain measures was found, which complicates interpretation. The increased levels of IL-1b and IL-8 in CSF of OA patients concur with the bulk of evidence on the role of central proinflammation in chronic pain states. No significant differences between OA patients and pain-free controls were noted with respect to CSF levels of IL-6 and IL-10. Complex Regional Pain Syndrome (CRPS). CRPS is an umbrella term encompassing various subtypes of disorders characterized by severe pain, which is spontaneously generated, or due to an inciting event, and associated with sensory, autonomic, and motor disturbances.82 Classification systems differ,83–85 and because the diagnosis is clinical, it is sometimes difficult to directly compare studies in this patient population. CRPS is divided into CRPS I, which arises without apparent nerve injury, and CRPS II which develops after damage to a peripheral nerve. Reported incidence numbers range between 5 and 20/100,000, and mean age at onset is 37 to 52 years.82 Differential diagnoses are extensive, and thorough investigation is needed to rule these out before settling on the CRPS diagnosis. The pathophysiology has not been unraveled, but psychological factors and immobilization often play a role. Dysfunction of the sympathetic nervous system, vasomotor disturbances, central neurogenic inflammation encompassing exaggerated neuropeptide and cytokine signaling, deep tissue microvascular abnormalities, and autoimmune mechanisms have all been highlighted.82 A systematic review and meta-analysis of the inflammatory aspects of CRPS concluded that the disorder is associated with a proinflammatory state in both blood, blister fluid and CSF.86 Four studies have been conducted on CSF cytokines in patients with CRPS.87–90 Alexander et al. conducted two similar studies, the first (n = 24) examining IL-1b, IL-6, and TNF-a, and the second (n = 22) expanding to include IL-4, IL-6, IL-8, IL-10, MCP-1, and a number of biochemical factors in CSF of patients with CRPS.87,88 The control group in both studies was heterogeneous, containing patients suffering from both painful and nonpainful conditions. IL-1b and IL-6 were significantly higher in the CRPS vs. control group, and there was a nonsignificant correlation between high IL-6 levels and high pain scores in the first study. In the second study,

IL-6 was significantly higher vs. all controls but the spondylolisthesis cohort, IL-4 significantly lower, IL-10 significantly lower in CRPS and painful control cohorts vs. nonpain controls. Interestingly, but not significantly proven vs. controls in this study, levels of MCP-1 and glial fibrillary acidic protein (GFAP, expressed by activated astrocytes) were elevated for all groups when compared to previously published results in neurologically healthy individuals. In 50% of the patients with CRPS, a pattern of elevated IL-6, MCP-1 or GFAP, NO metabolites, glutamate or calcium, and lowered IL-4 or IL-10 was found. Munts et al. examined patients with CRPS and dystonia about to receive IT treatment (n = 20).89 CSF IL-1b and IL-6, chemokines interferon-c inducible protein-10 and RANTES (regulated upon activation, normal T cell expressed and secreted), a selection of complement factors and an array of other molecules were analyzed. This study had a pain-free control group, and no significant differences between patients with CRPS and controls were found. A study by Backonja et al. examined a wide panel of cytokines: IL-1b, IL-6, IL-8, IL-10, IL-12, TNF-a, soluble TNF receptor (sTNFr), and IL-1 receptor antagonist in CSF and blood, in a group of chronic post-traumatic neuralgia (PTN) patients with CRPS features (n = 8), distal painful nondiabetic polyneuropathy patients (DPPN, n = 6), and healthy controls.90 The main significant findings were elevated sTNFr and low IL-10 in CSF and blood in the CRPS and DPPN patients. Interestingly, sTNFr (CSF, blood) and IL-1b (CSF) correlated positively, and IL-10 in both compartments correlated inversely, with pain scores. Results were provided for the chronic pain group as a whole and not reported separately for the patients with CRPS. Meta-analysis of the two Alexander studies and the Munts study, providing pooled effect estimates, indicated “significantly increased concentration with a large effect size for IL-1b, and a moderate effect size for IL-6 in the CSF of CRPS compared with controls”.86 It is noteworthy that none of the studies had patients with a disease duration of under 6 months. Central cytokine levels might vary both due to the heterogeneous nature of CRPS and duration of the disease, which complicates interpretation. However, although no elevation or reduction of CSF markers completely specific for CRPS has been found in human studies, a predominance of augmented proinflammatory and attenuated antiinflammatory cytokines and markers was found, providing evidence for central inflammation as a contributing factor in the pathophysiology of CRPS.

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Postherpetic Neuralgia (PHN). PHN is a neuropathic pain condition, the most common complication of herpes zoster (shingles), and defined as pain persisting for 90 days or more after the rash onset.91 About 30% experience an episode of herpes zoster in their lifetime and the incidence is higher among the elderly and immunocompromised patients, the latter group accounting for 8% of all herpes zoster episodes in the United States.91,92 The incidence of PHN follows the same pattern, being 18% in herpes zoster patients older than 50 years and 33% for those over 80 years.91 The character of pain is typically lancinating, burning, and associated with allodynia. PHN most commonly affects thoracic and cervical dermatomes, the ophthalmic division of trigeminal nerves, and other cranial nerves. Postmortem studies on six patients suffering from persistent PHN have shown findings of a subacute or chronic inflammatory process, ipsilateral dorsal horn atrophy and loss of DRG neurons, but the pathological evidence is presently limited.93,94 Harmful changes to the neural system are thought to be caused by varicella zoster reactivation and replication, inducing peripheral and central neural and inflammatory changes which contribute to peripheral and central sensitization.92 In two studies evaluating the effect of IT and epidural (ED) methylprednisolone (MEP) for intractable PHN, CSF cytokines have been examined.95,96 Kikuchi et al. published an uncontrolled, comparative study (IT vs. ED MEP treatment), where CSF IL-1b, IL-6, IL-8, and TNF-a were measured before treatment and 1 week post-treatment. While IL-1b, IL-6, and TNF-a were below the level of detection, IL-8 in this cohort (n = 25) of PHN patients was elevated compared to levels of healthy controls in other studies. IT MEP treatment was found to both significantly decrease the levels of IL-8 and provide satisfying and sustained pain relief in 12 of 13 patients. Through a randomized controlled trial, the same group of researchers published the largest study to date on a CSF cytokine in a human chronic pain population. The Kotani et al.96 study examined four injections of IT MEP and lidocaine vs. lidocaine only or no IT treatment, for the treatment of intractable PHN. The results from this study have been heavily criticized97–102 and a recent attempt to validate the findings was unsuccessful.103 However, according to the publication, CSF IL-8 was measured in 270 patients, showing significantly increased levels in PHN patients vs. controls. IL-8 levels prerandomization were inversely correlated with the duration of PHN, and IL-8 levels did not change over time in the control group or the IT

lidocaine group. Patients given IT MEP–lidocaine displayed a 50% decrease in IL-8 levels during treatment, which correlated with global pain relief (P < 0.001). Interestingly, elevated CSF IL-8 during acute herpes zoster episodes has been found to significantly predict PHN at 1 year.104 A small study (n = 10) by Rijsdijk et al. attempting to confirm the findings from the Kotani et al. study was prematurely terminated due to futility, clinical deterioration, and because new animal experimental evidence indicated neurotoxicity associated with IT MEP treatment.103,105 A number of CSF markers were analyzed, including IL-8, for which an increase was noted during treatment in the IT MEP group, in contrast to previously reported findings. Interestingly, MCP-1 decreased significantly after IT injections of MEP, and levels of most proinflammatory mediators (IL-1a, IL-1b, IL-6, and TNF-a) were undetectable in most samples. Taken together, the results highlight the potential role of a spinal proinflammatory state in PHN, evidenced by both elevated IL-8 levels in a large cohort of patients with severe and persistent PHN (mean duration 3.2 years) and the correlation between treatment response and lowered levels of IL-8, but evidence is not unambiguous. Fibromyalgia (FM). FM is characterized by chronic widespread pain and tender points (allodynia, hyperalgesia) and is frequently associated with other comorbid diseases, for example, headaches, affective disorders, insomnia, interstitial cystitis, and irritable bowel syndrome.106 Diagnostic criteria were revised in 2010,107 and global prevalence has been estimated to 2.7%.106 Central mechanisms are implicated in the etiology of FM, and quantitative sensory testing has shown lowered mechanical pain thresholds at nontender sites, and also reductions in electrical and thermal pain thresholds.108 The role of peripheral cytokines in FM is reviewed elsewhere.109 Giovengo et al.110 examined NGF and SP in the CSF of primary FM patients (n = 34), secondary FM patients (n = 15), a heterogeneous group of other chronic pain conditions (n = 10), and healthy controls (n = 35). Significantly elevated levels of NGF were found in the primary FM group, compared to all other groups, and SP was significantly elevated in all three chronic pain groups. It is noteworthy that NGF values exhibited a large variability in the FM group, and individual concentrations of NGF did not correlate with pain indices.


In a cross-sectional study, Kadetoff et al.111 examined serum IL-1b, IL-5, IL-6, IL-8, IL-10, and TNF-a, and CSF IL-1b and IL-8, in FM patients (n = 15) and in healthy (n = 15) and noninflammatory neurological symptom controls (n = 11). Significantly higher levels of IL-8 were found in both CSF and serum, and significantly lower levels of IL-1b, IL-5, and TNF-a in serum were found in FM patients compared with controls. IL-10 was not significantly affected in either group, but notable is that the anti-inflammatory cytokine IL-5 was lower in FM patients, and showed a negative correlation with ratings of depression, which corroborates previous findings in depressed 112,113 patients. Sarchielli et al. have conducted two cross-sectional studies in this pain population, one examining GDNF and somatostatin in CSF of FM patients (n = 20), chronic migraine (CM) and probable analgesic-abuse headache patients (n = 31), and healthy controls (n = 20)114; and one analyzing NGF, BDNF, and glutamate in CSF of FM patients (n = 20), CM patients (n = 20) and healthy controls (n = 20).115 In the first study, significantly lower CSF levels of GDNF and somatostatin were found in the FM patients compared to healthy controls (results related to CM are reported below). No correlation was found between levels of GDNF, somatostatin and duration or intensity of pain. In the second study, NGF, BDNF, and glutamate were significantly higher in FM patients compared to healthy controls. Further, a significant positive correlation between levels of BDNF, NGF, and glutamate were demonstrated, and NGF and BDNF levels were significantly correlated with duration of chronic pain and number of painful events/month in the FM group. Although not comparing levels of CSF cytokines/ neurotrophic factors to controls, a recent randomized trial on FM deserves to be mentioned, because effect of exercise on a number of CSF markers, such as NGF, SP, IL-6, IL-8, and matrix metalloproteinase (MMP) 3, was examined.116 Several findings were not pertinent to this review, but baseline levels of IL-6 were found to positively correlate with levels of SP and MMP3, and inversely correlate with levels of NGF. Thus, the results from 4 studies, including 104 FM patients, imply that elevated central levels of the neurotrophic factors NGF and BDNF, lowered levels of GDNF, and increased levels of IL-8, might contribute to the pathophysiology of FM, probably through increased central sensitization. Only one study showed a significant correlation between investigated central

markers and clinical parameters—increased levels of NGF and BDNF corresponded to duration of FM and frequency of painful events.115 Low Back Pain (LBP), Failed Back Surgery Syndrome (FBSS), and Lumbar Radiculopathy (LR). Chronic mechanical LBP is a condition of diverse etiology, which per definition exceeds a duration of 6 months, approximately afflicting about 8% of the adult US population.2 FBSS is an amorphous definition of several painful and disabling conditions that can manifest after lumbosacral spinal surgery, such as foraminal stenosis, nerve root compression, disk herniation, epidural fibrosis, instability, myofascial pain, or progressive degeneration of the facet joints. Between 5% and 50% of spinal surgery patients suffer from FBSS, resulting in chronic back pain with or without radicular lower extremity pain.117,118 LR is a painful condition resulting from nerve root compression, most commonly originating from lumbosacral disk degeneration.119 McCarthy et al. conducted a study on patients with FBSS treated with spinal cord stimulation (SCS) (n = 9), comparing baseline CSF levels of BDNF, MCP-1, and vascular endothelial growth factor (VEGF) with matched chronic LBP controls, and also longitudinally examining the impact of SCS on these markers.120 Patients with FBSS had significantly higher levels of BDNF and MCP-1 compared to controls, and levels of BDNF and VEGF correlated with reported pain. All of the patients with FBSS had positive responses to SCS, and 5 minutes of SCS resulted in a significant decrease in VEGF levels, indicating that SCS might exert its effect through neuroimmune modulation. The fact that patients with FBSS had been treated with SCS (for an undefined period of time) before entering the study obviously constitutes a major confounding factor regarding baseline values of the CSF markers. Zin et al. conducted a two-part study on chronic pain patients treated with IT opioids, examining CSF and plasma IL-6 and IL-10 both cross-sectionally (n = 50) and longitudinally.121 Although patients had various chronic pain diagnoses, a majority suffered from chronic mechanical LBP, and the average duration of IT treatment for the cross-sectional analysis was 5 years. CSF levels of IL-6 were significantly higher than levels of IL-10, but the plasma displayed converse results. Further, IL-6 was higher in CSF than plasma, and there were no significant correlations between plasma and CSF concentrations of the two cytokines. An inverse correlation was found between reported pain intensity and

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plasma, but not CSF, levels of IL-6 and IL-10. The longitudinal part (n = 10) investigated levels of IL-6 and IL-10 three times (at catheter implant, 4 to 7 days postimplant, at 3 months) over a 3-month time span after initiation of IT opioid treatment. CSF IL-6 increased significantly at 4 to 7 days, but then trended back toward pre-implant levels at 3 months. Throughout the 3 months, plasma IL-6 was lower than IL-10, CSF IL-10 levels remained unchanged (although several CSF IL-10 levels were nondetectable), and no correlations could be made between CSF IL-6, IL-10 and pain measures. Interestingly, when comparing the subjects having long duration of IT opioid treatment (5 years) to the subjects with short duration treatment (3 months), CSF IL-6 levels were five times higher in the group with long-term treatment, even though their analgesic morphine equivalents were only two and a half times higher, and pain scores did not differ. Nagashima et al.122 investigated the CSF concentrations of IL-1b, IL-6, and TNF-a in patients with LR (n = 19), cervical myelopathy (n = 21), and healthy controls (n = 6). LR patients had significantly increased levels of IL-6 compared to controls, but not compared to cervical myelopathy patients (for whom potential pain was not specified). For the LR patients, no correlation was found between IL-6 levels and clinical parameters such as symptom duration, and IL-1b and TNF-a were undetectable. Further, there was no correlation between underlying cause of LR, for example, spinal canal stenosis or disk herniation, and levels of IL-6. In a cross-sectional study by Ohtori et al.,123 CSF IL-6 and TNF-a were analyzed in LR (secondary to one level lumbar spinal stenosis) patients (n = 30) and age-matched controls (n = 10), not suffering from any spinal disorder. IL-6 was significantly higher in the LR group, compared to controls, and IL-6 levels correlated positively with the severity of stenosis, but not pain score, or walking ability. Unfortunately, TNF-a fell below the limit of detection. An uncontrolled study by Brisby et al. examined CSF and plasma IL-1b, IL-6, IL-8, IFN-c, and TNF-a in patients suffering from sciatica pain (n = 39, average duration 0.5 years) secondary to disk herniation, which is by far the most common cause of sciatica.124,125 IL-8 was elevated in 12/39 participants, and levels of IL-8 positively correlated with a short duration of pain and more pronounced disk herniation. As controls were lacking, comparison was made to reference values, but regarding the other cytokines, no significant findings were made.

Finally, a study by Capelle et al. examined CSF levels of NGF, BDNF, GDNF, and ciliary neurotrophic factor (CNTF) in patients suffering from neuropathic pain after spinal surgery (n = 10), chronic nociceptive LBP (n = 20), and normal pressure hydrocephalus (acting as nonpainful controls, n = 10).126 No significant differences were found between the groups for any of the neurotrophic factors, but there was a trend for lower GDNF concentrations in the neuropathic pain group. Currently, the results from this group of both nociceptive and neuropathic pain conditions, comprising 6 studies and 161 patients, are mixed—but some evidence supporting a role of increased central levels of BDNF, MCP-1, IL-6, and IL-8, in the pathophysiology of mechanical LBP, FBSS, and LR, exist. Further, the potential role of elevated central proinflammatory cytokines, for example, IL-6, in opioid tolerance, was highlighted. Chronic Migraine (CM) and Other Headaches. As defined by the International Headache Society (IHS), CM and chronic daily headache (CDH) must occur ≥15 days per month for at least 3 months, and new daily persistent headache (NDPH) must be present daily, and unremitting for over 3 months.127 CM is a prevalent (around 2% in the general population) and debilitating condition, where patients suffer not only from headache, but also from associated symptoms such as nausea, and photo- and phonophobia, strongly interfering with daily life.128 Two early Sarchielli et al.129 investigations examined CSF neurotrophic factors and neuropeptides in the CDH population. The first study (2001) analyzed NGF, SP, and CGRP in CDH subjects (n = 20) and healthy controls (n = 20), and significantly higher levels of all factors were found in the headache patients. Further, a positive correlation between NGF, SP, and CGRP, and duration of CDH and number of days with headache per month was found. The second study (2002) analyzed CSF NGF, BDNF, and glutamate in an almost identical study population, and results showed significant increases of all three mediators in the CDH group (n = 25).130 A positive correlation was noted between NGF, BDNF, and glutamate, and NGF and BDNF significantly correlated with duration of headache and number of days with headache per month. The 2005 and 2007 Sarchielli et al. studies previously cited included both FM and CM, and probable analgesic-abuse headache (PAAH) patients.114,115 Noted in findings similar to FM patients, CM patients also displayed significantly


lower levels of GDNF and somatostatin compared to controls, but no correlation could be made to pain scores or duration of CM.114 Congruent with results from 2001 and 2002, the 2007 investigation also showed significantly elevated levels of NGF, BDNF, and glutamate in CM patients compared to controls, as well as a positive correlation between levels of these markers and frequency of headaches and duration of CM.115 Finally, a study on treatment-resistant NDPH, CM and posttraumatic headache (PTH) patients (total n = 38), examining CSF and serum TNF-a in a cross-sectional manner, showed elevated CSF TNF-a in all subjects but one.131 To conclude, elevated central levels of NGF, BDNF, and TNF-a have been observed in CM and chronic headache patients in 5 studies comprising a total of 134 patients. Further, correlations between duration of disease, frequency of headaches and NGF and BDNF were found, strengthening the role of these factors in relation to the pathophysiology of CM and CDH. Other Chronic Pain Populations. Ludwig et al.132 conducted a study on a cohort of painful and nonpainful polyneuropathy (PNP) patients (n = 36) examining IL-6 and TNF-a in CSF and serum. No differences in cytokine profiles were found between the two groups. However, in the painful PNP group, patients with mechanical allodynia had higher levels of TNF-a in serum (P < 0.05), and for all PNP patients, serum levels of IL-6 and TNF-a correlated positively with severity of neuropathy. Prospective Therapeutic Strategies Given the abundance of preclinical evidence, and the emerging body of evidence from clinical studies, implicating central cytokines and neurotrophic factors in the pathophysiology of chronic pain, increasing attention has over the last decade been directed toward modulation of neuroimmune interactions. However, cytokines are involved in vital immune and physiologic functions, neurotrophic factors are essential for neuronal maintenance and regenerative processes, and glial cells exert crucial neuroprotective and neuroplasticity-affecting functions, urging a cautionary approach in attempts to modulate these systems. Pharmacotherapies inhibiting TNF-a (adalimumab, infliximab, etanercept) have been widely and successfully used in rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and enteritis133 and may

also alleviate pain in sciatica.134 Interestingly, case reports have shown benefit of TNF-a inhibition in CRPS.135 Epidural etanercept failed to provide pain relief in a recent study on lumbosacral radiculopathy,136 and preoperative subcutaneous etanercept did not affect rates of chronic postherniorrhaphy inguinal pain.137 Anti-IL-1 strategies, for example, anakinra, an IL-1 receptor antagonist, are currently used in RA,138 and hold promise in crystal arthritis,139 besides a number of systemic inflammatory diseases,140 but did not result in improved function or pain scores when given as single intra-articular injection in knee OA.141 The IL-6 inhibitor tocilizumab is a new treatment option in RA,142 but there are no ongoing studies trialing this drug for treatment of other pain conditions. Anti-IL-8 strategies have to date not been implemented in any clinical trials. A systemically administered MCP-1 receptor antagonist failed to show positive results in a clinical trial on patients with post-traumatic neuralgia.143 Interestingly, proinflammatory cytokines, for example, IL-1b and IL-6, are implicated in opioid tolerance and OIH. Opioid treatment, through activation of glial cells, triggers increase of proinflammatory cytokines, which oppose opioid analgesia, and in experimental settings, inhibition of proinflammatory cytokines has increased opioid efficacy and reduced tolerance and hyperalgesia.144,145 As described above, the study by Zin et al.121 provides plausible evidence for the role of a central cytokine, IL-6, in the development of opioid tolerance in humans. However, the phenomena of tolerance and OIH are complex, and for OIH, several molecular mechanisms have been proposed, involving spinal NMDA receptor activation, dynorphin, excitatory neuropeptides, decreased reuptake of neurotransmitters and descending facilitation arising from the rostral ventromedial medulla.146 It remains to be seen in future trials whether modulation of central cytokines could improve efficacy and reduce negative effects of long-term opioid treatment. Directly targeting and arresting glial cells are also an attractive approach, thus diminishing release of a wide array of cytokines and neurotrophic factors. Ibudilast, a phosphodiesterase inhibitor, selectively targets the synthesis of proinflammatory cytokines by microglia and has been used preclinically and clinically for the treatment of a multitude of inflammatory processes.147–150 In animal models, neuropathic pain behavior has been relieved,151 and ibudilast has also been shown to dramatically increase the analgesic potency of morphine and oxycodone when administered concurrently with

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the opioid.152 Clinical trials examining ibudilast in CM and medication overuse headache have been initiated (NCT01389193, NCT01317992). Minocycline, a broad-spectrum antibiotic, which also strongly blocks microglial activation, is also being pursued as a potential new treatment. Preclinical evidence as to its efficacy is convincing, but results from only one clinical trial have been published to date. In this trial, treatment with minocycline in the peri- and early postoperative period of patients undergoing lumbar discectomy failed to reduce the risk of CPSP.153 Several different strategies for intervening with the effects of NGF are theoretically plausible, but to date TrkA-antagonism or p75NTR-antagonism have not been pursued due to lack of sufficiently selective agents and risks related to inhibition of other kinases, which would have consequences for neurological function.70 Instead, anti-NGF monoclonal antibodies (tanezumab, fulranumab, fasinumab) have been the main focus for investigation, with most randomized controlled trials conducted in knee or hip OA chronic pain populations, but also in chronic LBP, chronic visceral pain syndromes, painful diabetic peripheral neuropathy, PHN, post-traumatic neuralgia, and cancer pain.154 It is unlikely that these antibodies cross the BSCB in significant amounts; thus, the main effect is exerted in the periphery. Efficacy, including pain reduction and functional improvement, has been shown for tanezumab in OA, but safety concerns related to destructive arthropathy, leading to total joint replacement, caused a temporary hold on all NGF-sequestering trials in 2010. Independent scrutiny found a treatment-induced dose-related risk of joint destruction (even in patients with no history of OA and in nonweight-bearing joints), especially when NSAID was used concurrently.154 Also, abnormal peripheral sensations (eg, paresthesia, hypoand hyperesthesia) have been associated with these treatments in about 5 to 10% of patients. Further antiNGF monoclonal antibody trials, implementing risk minimization strategies, are now ongoing, and it remains to be seen whether the analgesic efficacy/safety profile is favorable. To our knowledge, no specific antiBDNF strategies have been utilized in human chronic pain populations, but anti-NGF strategies indirectly affect BDNF through decreased expressional upregulation. Interestingly, in two small studies on patients with amyotrophic lateral sclerosis (ALS), aiming to harness the motor neuron protective effect of BDNF, IT BDNFinfusion did not evoke pain.155,156 Augmentation of GDNF-activity is being explored in the context of

neuropathic pain. Ligand specificity for different subtypes of the GDNF coreceptor exists, and interestingly, artemin (also known as neublastin) is specific for a subtype (GFRa3) only expressed in the PNS. Biogen Idec is pursuing this track and has after completion of two clinical phase 1 trials of artemin treatment in painful lumbar radiculopathy (NCT00961766, NCT01405833) initiated another phase 1 (NCT01842126) and a phase 2 trial (NCT01873404). Given the novel and potent nature of targeted anticytokine, antiglia, and antineurotrophic factor therapies, adverse events and risks, especially related to extended treatment, warrant concern. In the context of chronic pain in humans, most of the above-described approaches still lack strong evidence. Vigilance and careful monitoring of immune status, hematopoiesis, aberrant laboratory findings, and signs of serious infection and malignancy must be exercised in future trials. As described above, IT steroids have been used in trials on intractable PHN. However, safety issues surrounding this treatment warrant concern, involving inflammatory meningeal inflammatory reaction,105 and other serious complications.157 In the trial by Kotani et al.,96 no adverse events and excellent pain relief were reported, but the trial by Rijsdijk et al.,103 aiming to confirm these results, displayed clinical worsening and raised concerns regarding the safety associated with IT MEP. Today, IT steroids for PHN are not a widely recommended treatment. Preclinical evidence derived from various animal experimental models clearly demonstrate the potential of gene therapy approaches to treat chronic pain. Introduction, or induced overexpression, of endogenous analgesics (eg, b-endorphin, pro-enkephalin A, proopiomelanocortin), native anti-inflammatory cytokines (eg, IL-2, IL-10), or inhibition of transcription of nociceptive compounds (eg, NMDA receptor NR2B subunit siRNA, CGRP antisense) has been utilized in inflammatory, neuropathic, and bone cancer pain models, through nonviral and viral vectors.61–65,158,159 Results have so far been encouraging, but due to the novel nature of this treatment modality, and the associated risks inherent with gene therapy, only one study conducted in a human pain population has been published to date.160

DISCUSSION Evidence from preclinical investigations clearly establishes a link between peripheral nerve damage and


inflammation, CNS immune responses, and the development of chronic pain syndromes. The body of evidence of the role of central cytokines and neurotrophic factors in human chronic pain populations is presently limited, but emerging. Of the 25 studies reviewed, 17 found evidence in favor of increased CSF proinflammatory cytokines or neurotrophic factors (NGF, BDNF) in the examined chronic pain populations (Table 2). Results as to GDNF were mixed, with both elevated79 and lowered114 central levels. It is, however, important to bear in mind that the studies were limited in many aspects, very heterogeneous and examined different sets of cytokines and neurotrophic factors, making comparison and systematic review difficult. The most common findings were increased IL-1b,79,87,90 IL-6,87,88,121–123 IL-8,95,96,111,124 NGF,110,115,129,130 and BDNF.115,120,130 Significant dysregulation of antiinflammatory cytokines was only detected in one study (lowered IL-4, IL-10).88 In some of the studies, pain and functional measures were registered, but correlations between cytokines, neurotrophic factors, and pain severity were overall equivocal. For future research, several recommendations can be made. Through larger studies, including patients at different stages (disease duration) of the chronic pain condition, different central cytokine and neurotrophic factor patterns could be determined, which would potentially offer a neuroinflammatory profile of the specific pain state. For such a profiling, there are a number of measurement considerations. As changes in many inflammatory factors occur during neuroimmune activation, it will be necessary to analyze a multitude of factors, and considering the invasive nature of CSF samples, multiplex immunoassays would be ideal for these analyses.161 More sensitive assays are called for— in several of the studies, a number of markers were below the level of detection. Expansion of the research on CSF markers, both in healthy pain-free controls and

Table 2. Summary of Main Detected Significant Alterations of CSF Cytokines and Neurotrophic Factors According to Chronic Pain Condition Chronic Pain Condition

CSF Cytokines


OA CRPS PHN FM LBP, FBSS, LR CM, CDH

IL-1b↑, IL-8↑ IL-1b↑, IL-4↓, IL-6↑, IL-10↓, sTNFr↑ IL-8↑ IL-8↑ IL-6↑, IL-8↑, MCP-1↑ TNF-a↑

GDNF↑ N/A N/A BDNF↑, GDNF↓, NGF↑ BDNF↑ BDNF↑, NGF↑

chronic pain populations, would eliminate the current variability and uncertainty regarding reference values. Results from the studies included in this review reinforce the theory that peripheral cytokines do not readily cross the BSCB and that levels measured in the plasma and CSF represent local production, and that, based on prior studies,162,163 peripheral cytokines generally do not reflect central compartment underpinnings of chronic pain. However, considering the heterogeneity of the various chronic pain conditions analyzed in this review, the levels of CSF cytokines and neurotrophic factors might not fully reflect autochthonic production in the CNS, but could also partially be explained by a disruption of the BSCB. Conducting studies in more homogenous chronic pain groups would be of importance, as would expanding beyond the already described populations. To date, there is a scarcity of longitudinal studies examining CSF cytokines and neurotrophic factors. It is not difficult to understand why, because serial sampling would practically only be possible in patients with chronically implanted IT pumps, due to the ethical considerations in motivating serial lumbar punctures. However, the presence of an IT catheter causes neuroimmune activation in itself164 and the interpretation of samples from such patients are not uncomplicated, especially in the presence of IT opioid or other adjuvant treatment, further promoting spinal proinflammatory status.144 For future longitudinal studies on patients with indwelling IT catheters, it would be interesting with a virtually pain-free control group, for example, receiving IT baclofen therapy for spasticity, to discern the various effects of medication and the catheter itself. Also, the confounding effects of oral analgesics must be taken into account in these studies, because especially opioids are known to exert a proinflammatory effect. In most studies, analgesics were not discontinued, or were discontinued only a few hours before sampling, due to ethical considerations. However, in, for example, the study by Giovengo et al.,110 all analgesics were discontinued 2 weeks before assessment, minimizing the potential confounding effect. The lack of an adequately powered, matched, healthy, well-defined control group is an important and common flaw in several of the studies and in part this can be explained by the invasiveness of the procedure necessary for accessing CSF. Some of the studies used controls with painful conditions, complicating interpretation of results, or lacked controls. Also, a ubiquitous phenomenon in these studies is the lack of comprehensive pain, functional,

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sleep and psychological comorbidity scales and questionnaires. Correlating cytokine and neurotrophic factor profiles to these measures would generate important information on the interactions between immune and psychological responses and chronic pain. Chronic pain clearly exists as a product of multimodal physiologic dysfunction. Cytokines and neurotrophic factors alter pain processing and contribute strongly to the pathophysiology of chronic pain conditions, both through peripheral and central actions. Further and more comprehensive research in this novel field is warranted, to expand knowledge, and potentially (1) elucidate the pattern of dysregulation of factors most important for specific pain diagnoses, (2) identify markers for diagnosis, monitoring, prognosis, and severity grading of pain conditions, (3) further identify targets for intervention, and (4) unravel how and when it is optimal to intervene, to ameliorate suffering from detrimental chronic pain states.

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Nafcillin entry into human cerebrospinal fluid.