Nurcan Uçeyler

Publications of Nurcan Uçeyler

• The role of antidepressants in the management of fibromyalgia syndrome: a systematic review and meta-analysis.

  Authors: Winfried Häuser, Frederick Wolfe, Thomas Tölle, Nurcan Uçeyler, Claudia Sommer

  CNS drugs. 04/2012; 26(4):297-307.

  Background: The role of antidepressants in the management of fibromyalgia syndrome (FMS) still needs to be determined. Objective: The objective of this study was to provide a quantitative analysisBackground: The role of antidepressants in the management of fibromyalgia syndrome (FMS) still needs to be determined. Objective: The objective of this study was to provide a quantitative analysis (meta-analysis) of the efficacy and harms of antidepressants in the management of adult FMS patients. Data sources: The data sources used were the databases MEDLINE, SCOPUS and the Cochrane Central Register of Controlled Trials (until December 30, 2010), the reference lists of included articles, and the websites of the US National Institutes of Health (NIH) and the Pharmaceutical Research and Manufacturers of America (PhRMA). Study selection: Studies with a randomized controlled trial (RCT) design comparing any types of antidepressants with pharmacological placebo or head-to-head comparisons of different types of antidepressants in FMS patients were included. RCTs in which antidepressants were combined with any other defined treatment or antidepressants were tested against anything but drug placebo were excluded. Patients diagnosed with FMS according to predefined criteria of any age were included. To be included, studies had to assess at least one key domain of FMS (pain, sleep, fatigue, health-related quality of life [HRQOL]) as outcomes of efficacy and report total treatment discontinuation rates and/or dropout rates due to adverse events as outcomes for harms. Data extraction: Data were extracted according to protocols of previous systematic reviews on antidepressants in FMS. Methodology quality was assessed by the van Tulder score. Data synthesis: Standardized mean differences (SMD) were calculated for continuous outcomes by means and standard deviations and relative risks (RR) for 30% pain reduction and total dropout rate for comparisons of antidepressants with placebo. Examination of the combined results was performed by a random effects model. We used Cohen's categories to evaluate the magnitude of the effect size, calculated by SMD. Heterogeneity was tested by the I2 statistic. Thirty-five studies were included in the meta-analysis. The SMDs of serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) on pain, sleep, fatigue, depression and HRQOL were significant. Based on Cohen's categories, the effect size on pain was small and the ones on sleep, fatigue, depression and HRQOL were not substantial. 1481/3528 (42.0%) patients with SNRIs and 737/2304 (32.0%) patients with placebo reported a 30% pain reduction (number needed to treat [NNT] 10.0; 95% CI 8.00, 13.4; I2 = 4%). The RR of dropouts due to adverse events was 1.83 (95% CI 1.53, 2.18; I2 = 33%). The SMDs of selective serotonin reuptake inhibitors (SSRIs) on pain, sleep, depression and HRQOL were significant. Based on Cohen's categories, the effect sizes on pain, depression and HRQOL were small and the one on sleep not substantial. 72/198 (36.4%) patients with SSRIs and 40/194 (20.6%) patients with placebo reported a 30% pain reduction (NNT 6.3; 95% CI 4.1, 14.1). The RR of dropouts due to adverse events was 1.60 (95% CI 0.84, 3.04; I2 = 0%). The SMDs of tricyclic antidepressants (TCAs) on pain, sleep, fatigue and HRQOL were significant. Based on Cohen's categories, the effect sizes on pain and sleep were moderate and the ones on fatigue and HRQOL were small. 140/290 (48.3%) patients with TCAs and 70/252 (27.8%) patients with placebo reported a 30% pain reduction (NNT 4.9; 95% CI 3.5, 8.0). The RR of dropouts due to adverse events was 0.84 (95% CI 0.46, 1.52; I2 = 0%). Conclusions: The TCA amitriptyline and the SNRIs duloxetine and milnacipran are first-line options for the treatment of FMS patients. Physicians and patients should be realistic about the potential benefits of antidepressants in FMS. A small number of patients experience a substantial symptom relief with no or minor adverse effects. However, a remarkable number of patients dropout of therapy because of intolerable adverse effects or experience only a small relief of symptoms, which does not outweigh the adverse effects.

• Vasculitis-like neuropathy in amyotrophic lateral sclerosis unresponsive to treatment.

  Authors: Grazia Devigili, Nurcan Uçeyler, Marcus Beck, Karlheinz Reiners, Guido Stoll, Klaus V Toyka, Claudia Sommer

  Acta neuropathologica. 05/2011; 122(3):343-52.

  Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with variable involvement of other systems. A pathogenetic role of immune-mediated mechanisms has been suggested. WeAmyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with variable involvement of other systems. A pathogenetic role of immune-mediated mechanisms has been suggested. We retrospectively analyzed sural nerve pathology and the clinical course in 18 patients with ALS. These patients had undergone sural nerve biopsy because of clinical or neurophysiological signs indicating sensory involvement (ALS+). Eleven of the 18 ALS+ patients had inflammatory cell infiltrates (ALS(vasc)) resembling infiltrates seen in patients with vasculitic neuropathy. Data were compared with the 7 patients without vasculitic infiltrates (ALS(nonvasc)) and with those of 16 patients with isolated peripheral nerve vasculitis (NP(vasc)). Biopsy specimens were processed with standard histological stains and with immunohistochemistry for a panel of inflammatory markers, with the hypothesis that the composition of infiltrates should differ between ALS(vasc) and NP(vasc). Immunoreactive cells were quantified in a blinded manner. Unlike patients with NP(vasc), those with ALS(vasc) had only minor neurophysiological abnormalities in the sural nerve and, except for the infiltrates, almost normal nerve morphology on semithin sections. The difference in epineurial T cell count was significant between ALS(vasc) and ALS(nonvasc) (p = 0.031). Surprisingly, the cellular composition of epineurial infiltrates in sural nerve biopsies was indistinguishable between ALS(vasc) and NP(vasc) despite a significant difference in fiber pathology (p < 0.0001). Standard immunosuppressive treatment did not prevent clinical progression of the motor neuron disease in any of the patients with ALS(vasc). ALS(vasc) appears as a neuropathological subtype in ALS+ suggesting immune-mediated disease components but without response to standard immunosuppressive treatment.

• Serotonin transporter deficiency protects mice from mechanical allodynia and heat hyperalgesia in vincristine neuropathy.

  Authors: Niels Hansen, Nurcan Uçeyler, Florian Palm, Marek Zelenka, Lydia Biko, Klaus-Peter Lesch, Manfred Gerlach, Claudia Sommer

  Neuroscience letters. 03/2011; 495(2):93-7.

  Painful vincristine (VCR) neuropathy is a frequent and dose-limiting problem in cancer treatment. Here, we investigated how pain behavior is modulated in mice lacking the serotonin transporterPainful vincristine (VCR) neuropathy is a frequent and dose-limiting problem in cancer treatment. Here, we investigated how pain behavior is modulated in mice lacking the serotonin transporter (5-HTT-/- mice) after inducing neuropathy by intraperitoneal injections of VCR. We used standard tests for evoked pain, high performance liquid chromatography to measure serotonin (5-HT), and immunohistochemistry of L4/5 dorsal root ganglia (DRG) to assess neuronal injury and inflammation. After injections of VCR, 5-HTT-/- mice did not develop hypersensitivity to heat, in contrast to their wildtype (wt) littermates (p<0.05). Also, 5-HTT-/- mice recovered faster from mechanical hypersensitivity than wt mice (p<0.05). 5-HT levels were lower in the peripheral and central nervous tissue of vehicle or VCR-treated 5-HTT-/- mice compared to wt mice. VCR-treated mice had higher numbers of injured neurons as identified by immunostaining for activating transcription factor 3, and more immunoreactive macrophages in the L4/5 DRG than vehicle-treated mice. There was no difference between genotypes. Thus the 5-HTT-/- genotype did not protect mice from VCR-induced neuronal injury and macrophage infiltration in the DRG. Our results suggest that the reduced peripheral 5-HT levels of 5-HTT-/- mice in VCR neuropathy underlie the lack of heat hyperalgesia. Conversely, attenuation of mechanical allodynia in 5-HTT-/- mice may indicate reduced 5-HT-mediated facilitation in the central nervous system.

• Systematic review with meta-analysis: cytokines in fibromyalgia syndrome.

  Authors: Nurcan Uçeyler, Winfried Häuser, Claudia Sommer

  BMC musculoskeletal disorders. 01/2011; 12:245.

  To perform a systematic review and meta-analysis on cytokine levels in patients with fibromyalgia syndrome (FMS). Through December 2010 we systematically reviewed the databases PubMed, MEDLINE, andTo perform a systematic review and meta-analysis on cytokine levels in patients with fibromyalgia syndrome (FMS). Through December 2010 we systematically reviewed the databases PubMed, MEDLINE, and PsycINFO and screened the reference lists of 22 review articles for suitable original articles. Original articles investigating cytokines in patients with FMS were included. Data were extracted by two independent authors. Differences of the cytokine levels of FMS patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed applying methodological scores: modified Center of Evidence Based Medicine, Newcastle-Ottawa-Scale, and Würzburg Methodological Quality Score. Twenty-five articles were included investigating 1255 FMS patients and 800 healthy controls. Data of 13/25 studies entered meta-analysis. The overall methodological quality of studies was low. The results of the majority of studies were not comparable because methods, investigated material, and investigated target cytokines differed. Systematic review of the selected 25 articles revealed that FMS patients had higher serum levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8, and higher plasma levels of IL-8. Meta-analysis of eligible studies showed that FMS patients had higher plasma IL-6 levels compared to controls (SMD = -0.34 [-0.64, -0.03] 95% CI; p = 0.03). The majority of investigated cytokines were not different between patients and controls. The pathophysiological role of cytokines in FMS is still unclear. Studies of higher quality and with higher numbers of subjects are needed.

• Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients.

  Authors: Andreas Binder, Denisa May, Ralf Baron, Christoph Maier, Thomas R Tölle, Rolf-Detlef Treede, Achim Berthele, Frank Faltraco, Herta Flor, Janne Gierthmühlen [......] Walter Magerl, Christian Maihöfner, Helmut Richter, Roman Rolke, Andrea Scherens, Nurcan Uçeyler, Mike Ufer, Gunnar Wasner, Jihong Zhu, Ingolf Cascorbi

  PloS one. 01/2011; 6(3):e17387.

  Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes ofTransient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p = 0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p = 0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p = 0.006, p = 0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p = 0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients.

• TNF-α in CRPS and 'normal' trauma--significant differences between tissue and serum.

  Authors: Heidrun H Krämer, Tatiana Eberle, Nurcan Uçeyler, Ina Wagner, Thomas Klonschinsky, Lars P Müller, Claudia Sommer, Frank Birklein

  Pain. 10/2010; 152(2):285-90.

  Posttraumatic TNF-alpha signaling may be one of the factors responsible for pain and hyperalgesia in complex regional pain syndromes (CRPS). In order to further specify the role of TNF-alpha wePosttraumatic TNF-alpha signaling may be one of the factors responsible for pain and hyperalgesia in complex regional pain syndromes (CRPS). In order to further specify the role of TNF-alpha we investigated tissue (skin) and serum concentrations in three different patient groups: patients with osteoarthritis and planned surgery, with acute traumatic upper limb bone fracture waiting for surgery, and with CRPS I. Thirty patients (10 in each group) were recruited. Mean CRPS duration was 36.1 ± 8.1 weeks (range 8- 90 weeks). Skin punch biopsies were taken at the beginning of the surgery in osteoarthritis and fracture patients and from the affected side in CRPS patients. Blood samples were taken before the respective procedures. Skin and serum TNF-alpha levels were quantified by ELISA. Compared to patients with osteoarthritis, skin TNF-alpha was significantly elevated in CRPS (p<0.001) and fracture patients (p<0.04). Skin TNF-alpha in CRPS patients was higher than in patients with acute bone fracture (p<0.02). In contrast, serum TNF-alpha values were the same in osteoarthritis and CRPS, and lower in fracture patients (p<0.03). Our results indicate a local but not systemic increase of TNF-alpha in CRPS patients. This increase persists for months after limb trauma and may offer the opportunity for targeted treatment.

• MDL-28170 has no analgesic effect on CCI induced neuropathic pain in mice.

  Authors: Nurcan Uçeyler, Lydia Biko, Claudia Sommer

  Molecules (Basel, Switzerland). 05/2010; 15(5):3038-47.

  The calpain inhibitor MDL-28710 blocks the early local pro-inflammatory cytokine gene expression in mice after chronic constriction nerve injury (CCI). One-hundred-thirteen wild type mice of C57Bl/6JThe calpain inhibitor MDL-28710 blocks the early local pro-inflammatory cytokine gene expression in mice after chronic constriction nerve injury (CCI). One-hundred-thirteen wild type mice of C57Bl/6J background received CCI of the right sciatic nerve. Mechanical paw withdrawal thresholds and thermal withdrawal latencies were investigated at baseline and at 1, 3, and 7 days after CCI. Three application regimens were used for MDL-28170: a) single injection 40 min before CCI; b) serial injections of MDL-28170 40 min before and up to day three after CCI; c) sustained application via intraperitoneal osmotic pumps. The control animals received the vehicle DMSO/PEG 400. The tolerable dose of MDL-28170 for mice was 30 mg/kg body weight, higher doses were lethal within the first hours after application. Mechanical withdrawal thresholds and thermal withdrawal latencies were reduced after CCI and did not normalize after single or serial injections, nor with application of MDL-28170 via osmotic pumps. Although the calpain inhibitor MDL-28170 inhibits the early local cytokine upregulation in the sciatic nerve after CCI, pain behavior is not altered. This finding implies that local cytokine upregulation after nerve injury alone is only one factor in the induction and maintenance of neuropathic pain.

• Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice.

  Authors: Yong Chen, Michael K Boettger, Andreas Reif, Angelika Schmitt, Nurcan Uçeyler, Claudia Sommer

  Molecular pain. 03/2010; 6:13.

  Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying theseAlthough it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1beta), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1beta. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1beta, and IL-10 following CFA, overall corroborating the inhibitor data. These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.

• Skin biopsy as an additional diagnostic tool in non-systemic vasculitic neuropathy.

  Authors: Nurcan Uçeyler, Grazia Devigili, Klaus V Toyka, Claudia Sommer

  Acta neuropathologica. 03/2010; 120(1):109-16.

  Sural nerve biopsy is considered mandatory for diagnosing non-systemic vasculitic neuropathy (NSVN). This invasive technique may be associated with unpleasant sequelae and cannot easily be repeated.Sural nerve biopsy is considered mandatory for diagnosing non-systemic vasculitic neuropathy (NSVN). This invasive technique may be associated with unpleasant sequelae and cannot easily be repeated. Skin punch biopsy from an affected area may be a less invasive and repeatable diagnostic method. Here we assessed the potential diagnostic value of skin punch biopsies in NSVN by analyzing skin biopsies in 20 patients with sural nerve biopsy-proven NSVN and in 11 patients with non-inflammatory axonal neuropathy. As further controls, skin biopsies were studied in nine healthy volunteers. Five millimeter skin punch biopsies were taken under local anesthesia from the distal lateral calf and T cells and macrophages were quantified after immunostaining. The diagnostic sensitivity and specificity compared to sural nerve biopsy was determined using receiver operating characteristic (ROC) analysis. ROC analysis revealed that the highest sensitivity (94%) and specificity (79%) for NSVN was obtained when perivascular macrophages were quantified. Quantification of scattered T cells yielded a sensitivity and specificity of 65%. Inflammatory cells were very rare in controls. Quantification of inflammatory cells in skin biopsies may thus be a sensitive and specific additional tool for diagnosing NSVN.

• Deficiency of the negative immune regulator B7-H1 enhances inflammation and neuropathic pain after chronic constriction injury of mouse sciatic nerve.

  Authors: Nurcan Uçeyler, Kerstin Göbel, Sven G Meuth, Sonja Ortler, Guido Stoll, Claudia Sommer, Heinz Wiendl, Christoph Kleinschnitz

  Experimental neurology. 03/2010; 222(1):153-60.

  Peripheral nerve injury induces a profound local inflammatory response that involves T cells and macrophages and augments the generation of neuropathic pain. The mechanisms underlying immune cellPeripheral nerve injury induces a profound local inflammatory response that involves T cells and macrophages and augments the generation of neuropathic pain. The mechanisms underlying immune cell activation or inhibition in the peripheral nervous system, however, are unknown. The co-inhibitory molecule B7-H1 (PD-L1, CD274) attenuates immune cell proliferation and cytokine production and protects from inflammation-induced tissue damage. We analyzed the temporal gene expression profile of B7-H1 and different cytokines after chronic constriction injury (CCI) of the sciatic nerve, a lesion paradigm inducing neuropathic pain, by quantitative real-time polymerase chain reaction and immunohistochemistry in B7-H1(-/-) mice and wild-type (WT) controls. B7-H1 mRNA was markedly induced in WT nerves after CCI, and macrophages could be identified as major B7-H1 source. The proinflammatory mediators tumor necrosis factor alpha (TNFalpha) and monocyte chemoattractant protein-1 (MCP-1) displayed a strong, but transient expression in degenerating nerves on day 1 after CCI in WT mice, while a biphasic expression peak on day 1 and day 28 was found in B7-H1(-/-) mice. Overall, TNFalpha and MCP-1 levels in B7-H1-deficient nerves dramatically exceeded those in WT controls. In contrast, induction of the anti-inflammatory cytokine interleukin(IL)-10 was restricted to WT nerves. The observation that B7-H1 deficiency enhances inflammation upon CCI was further corroborated by immunohistochemistry showing increased numbers of T cells and macrophages in injured nerves from B7-H1(-/-) mice. Interestingly, mechanical hyperalgesia was more pronounced in the absence of B7-H1. Our study identifies B7-H1 as an important suppressor of the inflammatory response and neuropathic pain occurring after peripheral nerve injury.

• [Fibromyalgia syndrome: diagnostic criteria and treatment]

  Authors: Nurcan Uçeyler, Winfried Häuser, Claudia Sommer

  MMW Fortschritte der Medizin. 09/2009; 151(36):46-9.

• Treatment of fibromyalgia syndrome with gabapentin and pregabalin - A meta-analysis of randomized controlled trials.

  Authors: Winfried Häuser, Kathrin Bernardy, Nurcan Uçeyler, Claudia Sommer

  Pain. 06/2009;

  The efficacy of gabapentin (GPT) and pregabalin (PGB) in the treatment of fibromyalgia syndrome (FMS) was assessed. We screened MEDLINE, PsycINFO, SCOPUS, www.clinicaltrials.org, the Cochrane LibraryThe efficacy of gabapentin (GPT) and pregabalin (PGB) in the treatment of fibromyalgia syndrome (FMS) was assessed. We screened MEDLINE, PsycINFO, SCOPUS, www.clinicaltrials.org, the Cochrane Library (through October 2008), and the reference sections of original studies on GPT/PGB in FMS. Randomized controlled trials (RCTs) on the treatment of FMS with GPT and PGB were analyzed. Six out of 127 RCTs studying 2422 subjects on treatment with GPT (one study) or PGB (five studies) and 1056 subjects on placebo with a median treatment duration of 11weeks were included into the systematic review. Five studies were suitable for meta-analysis. Effects were summarized using standardized mean differences (SMD). There was strong evidence for a reduction of pain (SMD -0.28, 95% CI -0.36, -0.20; p<0.001), improved sleep (SMD -0.39, 95% CI -0.48, -0.39; p<0.001), and improved health-related quality of life (HRQOL) (SMD -0.30, 95% CI -0.46, -0.15; p<0.001), but not for depressed mood (SMD -0.12, 95% CI -0.30, 0.06; p=0.18). There was strong evidence for a non-substantial reduction of fatigue (SMD -0.16, 95% CI -0.23, -0.09, p<0.001) and of anxiety (SMD -0.18, 95% CI -0.27, -0.10; p<0.001). The external validity of the studies was limited because patients with severe somatic and mental disorders were excluded.

• Mode of action of cytokines on nociceptive neurons.

  Authors: Nurcan Uçeyler, Maria Schäfers, Claudia Sommer

  Experimental brain research. Experimentelle Hirnforschung. Experimentation cerebrale. 04/2009;

  Cytokines are pluripotent soluble proteins secreted by immune and glial cells and are key elements in the induction and maintenance of pain. They are categorized as pro-inflammatory cytokines, whichCytokines are pluripotent soluble proteins secreted by immune and glial cells and are key elements in the induction and maintenance of pain. They are categorized as pro-inflammatory cytokines, which are mostly algesic, and anti-inflammatory cytokines, which have analgesic properties. Progress has been made in understanding the mechanisms underlying the action of cytokines in pain. To date, several direct and indirect pathways are known that link cytokines with nociception or hyperalgesia. Cytokines may act via specific cytokine receptors inducing downstream signal transduction cascades, which then modulate the function of other receptors like the ionotropic glutamate receptor, the transient vanilloid receptors, or sodium channels. This receptor activation, either through amplification of the inflammatory reaction, or through direct modulation of ion channel currents, then results in pain sensation. Following up on results from animal experiments, cytokine profiles have recently been investigated in human pain states. An imbalance of pro- and anti-inflammatory cytokine expression may be of importance for individual pain susceptibility. Individual cytokine profiles may be of diagnostic importance in chronic pain states, and, in the future, might guide the choice of treatment.

• Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis.

  Authors: Winfried Häuser, Kathrin Bernardy, Nurcan Uçeyler, Claudia Sommer

  JAMA : the journal of the American Medical Association. 02/2009; 301(2):198-209.

  CONTEXT: Fibromyalgia syndrome (FMS) is a chronic pain disorder associated with multiple debilitating symptoms and high disease-related costs. Effective treatment options are needed. OBJECTIVES: ToCONTEXT: Fibromyalgia syndrome (FMS) is a chronic pain disorder associated with multiple debilitating symptoms and high disease-related costs. Effective treatment options are needed. OBJECTIVES: To determine the efficacy of antidepressants in the treatment of FMS by performing a meta-analysis of randomized controlled clinical trials. DATA SOURCES: MEDLINE, PsycINFO, Scopus, and the Cochrane Library databases were searched through August 2008. Reference sections of original studies, meta-analyses, and reviews on antidepressants in FMS were reviewed. STUDY SELECTION: Randomized placebo-controlled trials with tricyclic and tetracyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) were analyzed. DATA EXTRACTION AND DATA SYNTHESIS: Two authors independently extracted data. Effects were summarized using standardized mean differences (SMDs) by a random-effects model. RESULTS: Eighteen randomized controlled trials (median duration, 8 weeks; range, 4-28 weeks) involving 1427 participants were included. Overall, there was strong evidence for an association of antidepressants with reduction in pain (SMD, -0.43; 95% confidence interval [CI], -0.55 to -0.30), fatigue (SMD, -0.13; 95% CI, -0.26 to -0.01), depressed mood (SMD, -0.26; 95% CI, -0.39 to -0.12), and sleep disturbances (SMD, -0.32; 95% CI, -0.46 to -0.18). There was strong evidence for an association of antidepressants with improved health-related quality of life (SMD, -0.31; 95% CI, -0.42 to -0.20). Effect sizes for pain reduction were large for TCAs (SMD, -1.64; 95% CI, -2.57 to -0.71), medium for MAOIs (SMD, -0.54; 95% CI, -1.02 to -0.07), and small for SSRIs (SMD, -0.39; 95% CI, -0.77 to -0.01) and SNRIs (SMD, -0.36; 95% CI, -0.46 to -0.25). CONCLUSION: Antidepressant medications are associated with improvements in pain, depression, fatigue, sleep disturbances, and health-related quality of life in patients with FMS.

• A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome.

  Authors: Nurcan Uçeyler, Winfried Häuser, Claudia Sommer

  Arthritis and rheumatism. 10/2008; 59(9):1279-98.

  OBJECTIVE: To systematically review the efficacy of treatment of fibromyalgia syndrome (FMS) with antidepressants. METHODS: We screened Medline, PsychINFO, SCOPUS, and the Cochrane Library databasesOBJECTIVE: To systematically review the efficacy of treatment of fibromyalgia syndrome (FMS) with antidepressants. METHODS: We screened Medline, PsychINFO, SCOPUS, and the Cochrane Library databases (through October 2007) and the reference sections of original studies, meta-analyses, and evidence-based guidelines and recommendations on antidepressants in FMS. Randomized controlled trials (RCTs) on the treatment of FMS with antidepressants were analyzed. Inclusion criteria, study characteristics, quality, and all outcome measures were investigated. RESULTS: Twenty-six of 167 studies were included. The main outcome variables reviewed were pain, fatigue, sleep, depressiveness, and quality of life. Amitriptyline, studied in 13 RCTs, was efficient in reducing pain with a moderate magnitude of benefit (pain reduction by a mean of 26%, improvement in quality of life by 30%). Selective serotonin reuptake inhibitors (SSRIs) were studied in 12 RCTs, which also showed positive results, except for 2 studies on citalopram and 1 on paroxetine. Three RCTs on the dual serotonin and noradrenaline reuptake inhibitors (SNRIs) duloxetine and milnacipran and 1 of the 2 RCTs using the monoamine oxidase inhibitor moclobemide reported a positive result. The longest study duration was 12 weeks. CONCLUSION: Amitriptyline 25-50 mg/day reduces pain, fatigue, and depressiveness in patients with FMS and improves sleep and quality of life. Most SSRIs and the SNRIs duloxetine and milnacipran are probably also effective. Short-term treatment of patients with FMS using amitriptyline or another of the antidepressants that were effective in RCTs can be recommended. Data on long-term efficacy are lacking.

• Status of immune mediators in painful neuropathies.

  Authors: Nurcan Uçeyler, Claudia Sommer

  Current pain and headache reports. 07/2008; 12(3):159-64.

  Peripheral neuropathies of identical etiology can be painful or painless. The reason for this difference in clinical presentation is as yet unknown; however, immune mediators, particularly cytokines,Peripheral neuropathies of identical etiology can be painful or painless. The reason for this difference in clinical presentation is as yet unknown; however, immune mediators, particularly cytokines, may play a role. Cytokines are proteins that are produced by immune and nonimmune cells and are categorized as pro- and anti-inflammatory. The role of cytokines in the induction and maintenance of pain has been well established in animal models. Proinflammatory cytokines are mostly algesic, whereas anti-inflammatory cytokines have analgesic properties. Clinical research also gives evidence for the involvement of cytokines in painful and painless neuropathies. A proinflammatory cytokine profile seems to be associated with pain in peripheral neuropathies of different etiologies and in other painful disorders such as the complex regional pain syndrome. Specifically, an imbalance between pro- and anti-inflammatory cytokines may contribute to pain generation. A better understanding of the underlying pathophysiology may open new opportunities for the treatment of pain.

• New treatment options for fibromyalgia: critical appraisal of duloxetine.

  Authors: Nurcan Uçeyler, Martin Offenbächer, Frank Petzke, Winfried Häuser, Claudia Sommer

  Neuropsychiatric disease and treatment. 07/2008; 4(3):525-9.

  Fibromyalgia syndrome (FMS) is a chronic condition characterized by widespread pain, tender points, fatigue, and sleep disturbance. FMS leads to high disability levels, poor quality of life, andFibromyalgia syndrome (FMS) is a chronic condition characterized by widespread pain, tender points, fatigue, and sleep disturbance. FMS leads to high disability levels, poor quality of life, and extensive use of medical care. Effective pharmacological treatment options are rare, and treatment effects are often of limited duration. Duloxetine is a new selective serotonin and norepinephrine reuptake inhibitor that is licensed for the treatment of pain in diabetic neuropathy. So far two randomized, placebo-controlled trials have investigated the short-term safety and efficacy of duloxetine 60 mg/day and 120 mg/day in patients suffering from FMS over a period of 12 weeks. Both dosages were superior to placebo in pain relief, and improvement in quality of life and depressive symptoms. The analgesic effect was largely independent of the antidepressant action of duloxetine. The higher dose of 120 mg/day further reduced the tender point count and elevated the tender point pain thresholds. Only mild to moderate adverse effects were reported. Duloxetine 60 mg/day and 120 mg/day has proven to be beneficial in the treatment of FMS symptoms. As true for other antidepressants further studies are needed to assess the long-term efficacy and safety of duloxetine as an additional pharmacological treatment option in FMS.

• Cytokine regulation in animal models of neuropathic pain and in human diseases.

  Authors: Nurcan Uçeyler, Claudia Sommer

  Neuroscience letters. 07/2008; 437(3):194-8.

  Cytokines are soluble proteins secreted mainly by immune cells and are key players in the induction and maintenance of pain. Pro-inflammatory cytokines are mostly algesic, while anti-inflammatoryCytokines are soluble proteins secreted mainly by immune cells and are key players in the induction and maintenance of pain. Pro-inflammatory cytokines are mostly algesic, while anti-inflammatory cytokines have analgesic properties. After the role of cytokines was shown in diverse animal models of pain, interest arose in the systemic and local regulation of cytokines in human pain states. Most clinical studies give evidence for an imbalance between pro- and anti-inflammatory cytokines in neuropathic and other pain states with pronounced pro-inflammatory cytokine profiles. Anti-cytokine treatment gives encouraging preliminary results and supports the notion of a crucial role of cytokines also in human pain states. Further research is needed for a better understanding of the mechanisms linking altered cytokine profiles to the sensation of pain.

• Early cytokine gene expression in mouse CNS after peripheral nerve lesion.

  Authors: Nurcan Uçeyler, Andreas Tscharke, Claudia Sommer

  Neuroscience letters. 06/2008; 436(2):259-64.

  The generation and maintenance of pain after peripheral nerve injury are thought to be influenced by cytokine signaling. Chronic constriction injury (CCI) to mouse sciatic nerve leads to an earlyThe generation and maintenance of pain after peripheral nerve injury are thought to be influenced by cytokine signaling. Chronic constriction injury (CCI) to mouse sciatic nerve leads to an early local upregulation of pro-inflammatory cytokines already 1 h after the lesion. The early regulation of cytokines in pain related CNS areas is largely unknown. We investigated cytokine regulation in the lumbar spinal cord, hypothalamus, thalamus, hippocampus, and frontal cortex in C57Bl/6J mice after lesioning the right sciatic nerve by CCI. The gene expression of tumor necrosis factor-alpha (TNF), interleukin (IL)-1beta, IL-4, and IL-10 was analyzed by quantitative real-time-PCR from 1 to 12 h after surgery or until values were back to baseline. CCI led to an early downregulation of TNF and IL-1beta mRNA in distinct brain areas and in the lumbar spinal cord with a maximum decrease within the first 6h after CCI. The reduction of TNF mRNA was inhibited by the NMDA receptor antagonist (+)-MK-801, while the calpain inhibitor MDL-28170 had no effect. Our results suggest an early cytokine regulation in the CNS after peripheral nerve lesion, which is opposite in direction to that in the periphery and which is partly mediated by the NMDA receptor system.

• Differential expression patterns of cytokines in complex regional pain syndrome.

  Authors: Nurcan Uçeyler, Tatiana Eberle, Roman Rolke, Frank Birklein, Claudia Sommer

  Pain. 11/2007; 132(1-2):195-205.

  Complex regional pain syndromes (CRPS) are characterized by persistent and severe pain after trauma or surgery. Neuro-immune alterations are assumed to play a pathophysiological role. Here we set outComplex regional pain syndromes (CRPS) are characterized by persistent and severe pain after trauma or surgery. Neuro-immune alterations are assumed to play a pathophysiological role. Here we set out to investigate whether patients with CRPS have altered systemic pro- and anti-inflammatory cytokine profiles compared to controls on mRNA and protein level. We studied blood cytokine mRNA and protein levels of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF), interleukin-2 (IL-2) and IL-8 and the anti-inflammatory cytokines IL-4, IL-10, and transforming growth factor-beta1 (TGF beta 1) in 40 prospectively recruited patients with CRPS I, two patients with CRPS II, and 34 controls. Quantitative real-time PCR and enzyme linked immunosorbent assay were used. Additionally, the patients underwent quantitative sensory testing and were assessed with the McGill pain questionnaire and the Hospital anxiety and depression scale. Patients with CRPS had higher blood TNF and IL-2 mRNA levels (p=0.005; p=0.04) and lower IL-8 mRNA levels (p<0.001) than controls. The mRNA for the anti-inflammatory cytokines IL-4 and IL-10 was reduced in the patient group (p=0.004; p=0.006), whereas TGF beta 1 mRNA levels did not differ between groups. These results were paralleled by serum protein levels, except for TGF beta 1, which was reduced in patients with CRPS, and for IL-8, which gave similar protein values in both groups. Sensory testing showed a predominant loss of small fiber-related modalities in the patient group. The shift towards a pro-inflammatory cytokine profile in patients with CRPS suggests a potential pathogenic role in the generation of pain.