The role of cytokines and chemokines in the maintenance of chronic pain-a pilot study.

Introduction: The immune system is believed to be important in the initiation and maintenance of chronic pain. Objectives: The aim was to investigate whether patients with chronic painful polyneuropathy (PP) differ in cytokine profiles of serum and/or cerebrospinal fluid (CSF) compared with pain-free controls. Methods: Thirty-nine patients (16 women and 23 men, mean age, 69.2 ± 12.7 years, range 41-92 years) with PP (mean duration 43 ± 48.3 months) were phenotyped with quantitative sensory testing and electroneurography, and serum and CSF samples were analyzed by 40-multiplexed, bead-based cytokine immunoassays. Results were compared with 36 age- and gender-matched patients with normal pressure hydrocephalus and absence of abnormal CSF findings. Results: Compared with controls, patients with PP had lower concentrations of several proinflammatory and anti-inflammatory chemokines and cytokines in CSF, and others showed the same tendency, among these were tumor necrosis factor-α (14.1 ± 10.0 vs 23.9 ± 16.4 pg/mL, P < 0.005), interleukin (IL)-2 (0.6 ± 0.4 vs 1.2 ± 0.6 pg/mL, P < 0.0001), IL-6 (4.7 ± 6.8 vs 7.3 ± 9 pg/mL, P = 0.001), and IL-10 (7.5 ± 6.8 vs 16.8 ± 19.2 pg/mL, P < 0.01), whereas no differences were observed in serum. Conclusion: Results suggest that (1) inflammatory mediators play a minor role in the maintenance of chronic pain in contrast to initiation of acute pain, (2) chemokines/cytokines are downregulated in chronic pain, or (3) chemokines/cytokines have a protective role for nerve regeneration that is disturbed in patients with chronic pain.

Pain matters for central sensitization: sensory and psychological parameters in patients with fibromyalgia syndrome.

INTRODUCTION: Patients suffering from fibromyalgia syndrome (FMS) are heterogenous. They often present with sensory abnormalities and comorbidities. OBJECTIVES: We aimed to answer the following questions: (1) Is there a specific somatosensory profile in our patient cohort? (2) Can we detect subgroups characterized by a specific combination of sensory and psychological features? and (3) Do psychological parameters influence sensory signs? METHODS: In 87 patients with FMS quantitative sensory testing was performed on the hand and evaluated in combination with questionnaire results regarding pain, psychological comorbidities, sleep, and functionality. RESULTS: Patients presented different somatosensory patterns, but no specific subgroups regarding sensory signs and psychological features were detected. Hypersensitivity for noxious mechanical and thermal stimuli and hyposensitivity for nonnoxious mechanical stimuli were the most prominent features. Thirty-one percent of patients showed signs of central sensitization as indicated by abnormally increased pinprick hyperalgesia or dynamic mechanical allodynia. Central sensitization was associated with higher pain intensities (P < 0.001). Only a small influence of psychiatric comorbidities on mechanical pain sensitivity (P = 0.044) and vibration detection (P = 0.028) was found, which was partly associated with high pain intensities. A small subgroup of patients (11.4%) demonstrated thermal hyposensitivity (loss of small-fiber function). CONCLUSION: Patients with FMS showed various somatosensory abnormalities. These were not significantly influenced by psychological comorbidities. Signs for central sensitization were detected in about one-third of patients and associated with higher pain intensities. This supports the notion of central sensitization being a major pathophysiological mechanism in FMS, whereas small-fiber loss may be less important.

Changes of Somatosensory Phenotype in the Course of Disease in Osteoarthritis Patients.

To investigate sensory changes, physical function (pF), quality of life (QoL) and pain intensity of patients with osteoarthritis (OA) in the natural course of disease, and patients undergoing total joint replacement therapy (TJR) 31 (20 females, mean age 64.6 ± 10.4 years), patients with OA were investigated with questionnaires and quantitative sensory testing (QST) in the area of referred pain at the thigh at baseline and follow-up 22-49 weeks later; changes were analyzed separately for patients with (n = 13) and without TJR (n = 18). In patients without TJR pain intensity, pF, QoL did not improve, and increased pain sensitivity to cold and a stronger loss of detection were observed. In patients after TJR, however, a reduction in mechanical pain sensitivity and allodynia occurred in accordance with a reduction of pain intensity and improvement of functionality while QoL did not improve. Additionally, an increased sensitivity to heat pain and a more pronounced loss of mechanical detection could be observed in this group. TJR seems to stop peripheral pain input leading to a reduction of pain intensity and central sensitization, but surgery-induced sensory changes such as peripheral sensitization and loss of detection occur. Furthermore, TJR has favorable effects on pain intensity and functionality but not QoL.

Clinical Manifestation of Acute, Subacute, and Chronic Low Back Pain in Different Age Groups: Low Back Pain in 35,446 Patients.

BACKGROUND: Low back pain (LBP) is a major healthcare problem causing tremendous economic costs. METHODS: Clinical manifestation of LBP was characterized in 35,446 patients. We focused on the comparison of the acute, subacute, and chronic LBP stage with regard to patients' ages, based on epidemiologic and clinical questionnaires (eg, painDETECT Questionnaire, Pain Disability Index), pain intensity, pain descriptors, and functional impairment. RESULTS: We found that neuropathic components were most frequent in chronic LBP patients at the ages of 51 to 60 years. Elderly LBP patients showed a decrease in neuropathic and an increase in nociceptive pain. The most frequently reported pain descriptors were "pressure pain" and "pain attacks" through all stages of LBP, whereas "burning" and "prickling" were most frequent in the chronic stage. Patients after back surgery presented neuropathic pain symptoms most frequently and had the highest amount of pain medication intake. CONCLUSIONS: Burning and prickling were revealed as possible indicators for LBP chronicity. Combined with pain attacks and pressure pain, these 4 pain descriptors might be a promising adjunct to pain intensity in terms of outcome parameters for future LBP studies. The decrease of neuropathic pain syndromes in the elderly might be explained by degenerative processes. The presented work provides important insights on LBP management in the acute, subacute, and chronic stages.

A-Fibers Mediate Cold Hyperalgesia in Patients with Oxaliplatin-Induced Neuropathy.

Cold hyperalgesia is a common side effect of oxaliplatin treatment; still, the pathophysiological and molecular mechanisms as well as the contribution of different primary afferent fiber systems are unclear. Therefore, patients with oxaliplatin-induced acute neuropathy with (n = 6) and without (n = 7) cold hyperalgesia were tested by applying a preferential blockade of peripheral myelinated A-fiber afferents in combination with quantitative sensory testing. Additionally, an interview-based questionnaire assessed the severity of symptoms and the impact on daily activities. Results indicate a deficit of cold perception in patients without cold hyperalgesia compared to patients with cold hyperalgesia prior to A-fiber blockade. In patients with cold hyperalgesia, a preferential blockade of A-fibers abolished cold hyperalgesia. This suggests that oxaliplatin-induced cold hyperalgesia is mediated by A-fibers and that a deficit in A-fiber function might prevent the development of cold hyperalgesia. The work supports findings in rodents and in human sural nerve biopsies indicating that oxaliplatin interferes with axonal ion conductance in intact A-fibers by sensitizing potassium and/or sodium channels. Drugs that act on these molecular targets might be of potential value to treat oxaliplatin-induced cold hyperalgesia.

DOLORisk: study protocol for a multi-centre observational study to understand the risk factors and determinants of neuropathic pain.

Background: Neuropathic pain is an increasingly prevalent condition and has a major impact on health and quality of life. However, the risk factors for the development and maintenance of neuropathic pain are poorly understood. Clinical, genetic and psychosocial factors all contribute to chronic pain, but their interactions have not been studied in large cohorts. The DOLORisk study aims to study these factors. Protocol: Multicentre cross-sectional and longitudinal cohorts covering the main causes leading to neuropathic pain (e.g. diabetes, surgery, chemotherapy, traumatic injury), as well as rare conditions, follow a common protocol for phenotyping of the participants. This core protocol correlates answers given by the participants on a set of questionnaires with the results of their genetic analyses. A smaller number of participants undergo deeper phenotyping procedures, including neurological examination, nerve conduction studies, threshold tracking, quantitative sensory testing, conditioned pain modulation and electroencephalography. Ethics and dissemination: All studies have been approved by their regional ethics committees as required by national law. Results are disseminated through the DOLORisk website, scientific meetings, open-access publications, and in partnership with patient organisations. Strengths and limitations: Large cohorts covering many possible triggers for neuropathic painMulti-disciplinary approach to study the interaction of clinical, psychosocial and genetic risk factorsHigh comparability of the data across centres thanks to harmonised protocolsOne limitation is that the length of the questionnaires might reduce the response rate and quality of responses of participants.

Neuropathic Pain.

Diagnosing neuropathic pain and distinguishing it from nociceptive pain can be challenging, but is essential because both forms of pain require different treatment strategies. The diagnosis of neuropathic pain is primarily based on clinical findings. Therefore, a careful, focused history and an examination of the signs characteristic of neuropathic pain are crucial. Imaging techniques and electrophysiological examinations, as well as punch skin biopsy can support the clinical diagnosis. Ideally, treatment should be individualized using a mechanism-based approach. However, current treatments are usually dispensed without precision, and calcium-channel-acting modulators (pregabalin, gabapentin), tricyclic antidepressants, and serotonin-noradrenalin reuptake inhibitors (duloxetine, venlafaxine) represent first-line treatment options for neuropathic pain. Although neurostimulation techniques for the treatment of refractory chronic pain have become more important, most evidence of long-term effectiveness and safety is still limited, which strengthens the need for larger randomized controlled trials before final recommendations can be made.