Nurcan Üçeyler

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes

&NA; Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non‐nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non‐nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind‐up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism‐based classification feasible.

Treatment of Fibromyalgia Syndrome With Antidepressants: A Meta-analysis

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 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.

Small fibre pathology in patients with fibromyalgia syndrome

Fibromyalgia syndrome is a clinically well-characterized chronic pain condition of high socio-economic impact. Although the pathophysiology is still unclear, there is increasing evidence for nervous system dysfunction in patients with fibromyalgia syndrome. In this case-control study we investigated function and morphology of small nerve fibres in 25 patients with fibromyalgia syndrome. Patients underwent comprehensive neurological and neurophysiological assessment. We examined small fibre function by quantitative sensory testing and pain-related evoked potentials, and quantified intraepidermal nerve fibre density and regenerating intraepidermal nerve fibres in skin punch biopsies of the lower leg and upper thigh. The results were compared with data from 10 patients with monopolar depression without pain and with healthy control subjects matched for age and gender. Neurological and standard neurophysiological examination was normal in all patients, excluding large fibre polyneuropathy. Patients with fibromyalgia syndrome had increased scores in neuropathic pain questionnaires compared with patients with depression and with control subjects (P < 0.001 each). Compared with control subjects, patients with fibromyalgia syndrome but not patients with depression had impaired small fibre function with increased cold and warm detection thresholds in quantitative sensory testing (P < 0.001). Investigation of pain-related evoked potentials revealed increased N1 latencies upon stimulation at the feet (P < 0.001) and reduced amplitudes of pain-related evoked potentials upon stimulation of face, hands and feet (P < 0.001) in patients with fibromyalgia syndrome compared to patients with depression and to control subjects, indicating abnormalities of small fibres or their central afferents. In skin biopsies total (P < 0.001) and regenerating intraepidermal nerve fibres (P < 0.01) at the lower leg and upper thigh were reduced in patients with fibromyalgia syndrome compared with control subjects. Accordingly, a reduction in dermal unmyelinated nerve fibre bundles was found in skin samples of patients with fibromyalgia syndrome compared with patients with depression and with healthy control subjects, whereas myelinated nerve fibres were spared. All three methods used support the concept of impaired small fibre function in patients with fibromyalgia syndrome, pointing towards a neuropathic nature of pain in fibromyalgia syndrome.

Differential expression patterns of cytokines in complex regional pain syndrome.

Abstract 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 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‐α (TNF), interleukin‐2 (IL‐2) and IL‐8 and the anti‐inflammatory cytokines IL‐4, IL‐10, and transforming growth factor‐β1 (TGFβ1) 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 TGFβ1 mRNA levels did not differ between groups. These results were paralleled by serum protein levels, except for TGFβ1, 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.

Differential expression of cytokines in painful and painless neuropathies

Background: Pain is a common symptom in peripheral neuropathies. The factors determining why some peripheral neuropathies are painful and others are not are incompletely understood. Pro-inflammatory cytokines have been implicated to play a crucial role in the generation of pain. Objective: To investigate whether cytokine profiles differ between patients with painful or painless neuropathy. Methods: In this prospective study, we analyzed blood mRNA and protein levels of the pro-inflammatory cytokines interleukin-2 (IL-2) and tumor necrosis factor-α (TNF) and the anti-inflammatory cytokines IL-4 and IL-10 in 32 patients with painful neuropathy, 20 patients with painless neuropathy, and 38 healthy control subjects, using quantitative real-time PCR and ELISA. Results: Patients with a painful neuropathy had about twofold higher IL-2 mRNA (p = 0.001) and TNF mRNA (p < 0.0001) and protein levels (p = 0.009) than healthy control subjects and about twofold higher IL-2 and TNF mRNA (p = 0.03; p = 0.001) and protein levels (p = 0.04; p = 0.04) than patients with painless neuropathy. In contrast, mRNA levels of the anti-inflammatory cytokine IL-10 were about twofold higher in patients with painless neuropathy than in patients with painful neuropathy (p = 0.001) and controls (p = 0.004). IL-4 protein levels were 20-fold higher in patients with painless neuropathy (p < 0.0001) and 17-fold higher in patients with painful neuropathy (p < 0.0001) than in healthy control subjects. Conclusions: A pro-inflammatory cytokine profile seems to be associated with pain in the setting of a peripheral neuropathy, corroborating findings in animal models with experimental painful neuropathies. This may have implications for future treatment strategies.

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

ABSTRACT 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 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 11 weeks 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.

Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition

Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces stiff person syndrome-like symptoms in rats, including stiffness and muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-amphiphysin immunoglobulin G was internalized into neurons by an epitope-specific mechanism and colocalized in vivo with presynaptic vesicular proteins, as shown by stimulation emission depletion microscopy. Neurons from amphiphysin deficient mice that did not internalize the immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic protein AP180 and by defective loading of FM 1-43, a styryl dye used to label cell membranes. Incubation of cultured neurons with anti-amphiphysin immunoglobulin G reduced basal and stimulated release of γ-aminobutyric acid substantially more than that of glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with antibodies against amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of stiff person syndrome at the molecular level and show that autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key protein by disturbing vesicular endocytosis.

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

OBJECTIVE 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.

Emotional, physical, and sexual abuse in fibromyalgia syndrome: A systematic review with meta‐analysis

To systematically assess the potential association of fibromyalgia syndrome (FMS) with emotional, physical, and sexual abuse.

Mode of action of cytokines on nociceptive neurons

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, 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.