Antje Beyer

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values.

Abstract The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age‐ and gender‐matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus/response‐functions for pinprick and dynamic mechanical allodynia, and pain summation (wind‐up ratio). QST parameters were region specific and age dependent. Pain thresholds were significantly lower in women than men. Detection thresholds were generally independent of gender. Reference data were normalized to the specific group means and variances (region, age, gender) by calculating z‐scores. Due to confidence limits close to the respective limits of the possible data range, heat hypoalgesia, cold hypoalgesia, and mechanical hyperesthesia can hardly be diagnosed. Nevertheless, these parameters can be used for group comparisons. Sensitivity is enhanced by side‐to‐side comparisons by a factor ranging from 1.1 to 2.5. Relative comparisons across body regions do not offer advantages over absolute reference values. Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes.

Immediate effects of dry needling and acupuncture at distant points in chronic neck pain: results of a randomized, double-blind, sham-controlled crossover trial

&NA; To evaluate immediate effects of two different modes of acupuncture on motion‐related pain and cervical spine mobility in chronic neck pain patients compared to a sham procedure. Thirty‐six patients with chronic neck pain and limited cervical spine mobility participated in a prospective, randomized, double‐blind, sham‐controlled crossover trial. Every patient was treated once with needle acupuncture at distant points, dry needling (DN) of local myofascial trigger points and sham laser acupuncture (Sham). Outcome measures were motion‐related pain intensity (visual analogue scale, 0–100 mm) and range of motion (ROM). In addition, patients scored changes of general complaints using an 11‐point verbal rating scale. Patients were assessed immediately before and after each treatment by an independent (blinded) investigator. Multivariate analysis was used to assess the effects of true acupuncture and needle site independently. For motion‐related pain, use of acupuncture at non‐local points reduced pain scores by about a third (11.2 mm; 95% CI 5.7, 16.7; P=0.00006) compared to DN and sham. DN led to an estimated reduction in pain of 1.0 mm (95% CI −4.5, 6.5; P=0.7). Use of DN slightly improved ROM by 1.7° (95% CI 0.2, 3.2; P=0.032) with use of non‐local points improving ROM by an additional 1.9° (95% CI 0.3, 3.4; P=0.016). For patient assessment of change, non‐local acupuncture was significantly superior both to Sham (1.7 points; 95% CI 1.0, 2.5; P=0.0001) and DN (1.5 points; 95% CI 0.4, 2.6; P=0.008) but there was no difference between DN and Sham (0.1 point; 95% CI −1.0, 1.2; P=0.8). Acupuncture is superior to Sham in improving motion‐related pain and ROM following a single session of treatment in chronic neck pain patients. Acupuncture at distant points improves ROM more than DN; DN was ineffective for motion‐related pain.

White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion‐tensor and volumetric imaging study

OBJECTIVE To use a combination of magnetic resonance diffusion-tensor imaging (MR-DTI) and MR imaging of voxel-based morphometry (MR-VBM) in patients with fibromyalgia syndrome (FMS) to determine microstructural and volume changes in the central neuronal networks involved in the sensory-discriminative and affective-motivational characteristics of pain, anxiety, memory, and regulation of the stress response. METHODS Thirty female patients with FMS and 30 healthy female control subjects were studied. Predefined areas of the brain were measured for volume of gray matter by MR-VBM and for diffusivity and fractional anisotropy (FA) by MR-DTI. Higher FA values and reduced diffusivity are thought to reflect increased complexity of brain-tissue microstructure. RESULTS MR-VBM and MR-DTI demonstrated a striking pattern of changes in brain morphology in patients with FMS. Both thalami, the thalamocortical tracts, and both insular regions showed significant decreases in FA. In contrast, increases in FA and decreases in gray matter volume were seen in the postcentral gyri, amygdalae, hippocampi, superior frontal gyri, and anterior cingulate gyri. Increased pain intensity scores were correlated with changes in MR-DTI measurements in the right superior frontal gyrus. Increased fatigue was correlated with changes in the left superior frontal and left anterior cingulate gyrus, and self-perceived physical impairment was correlated with changes in the left postcentral gyrus. Higher intensity scores for stress symptoms were correlated negatively with diffusivity in the thalamus and FA in the left insular cortex. No relationship was found between MR-VBM measurements and symptom intensity scores. CONCLUSION MR-DTI allows the visualization of microstructural changes in the brain of patients with FMS, appears to be more sensitive than MR-VBM, and may serve as an additional diagnostic technique in FMS and probably other dysfunctional pain syndromes.

Anandamide and neutrophil function in patients with fibromyalgia

Fibromyalgia (FM) is a common stress-related painful disorder. There is considerable evidence of neuroimmunologic alterations in FM which may be the consequence of chronic stress and pain or causally involved in the development of this disorder. The endocannabinoid system has been shown to play a pivotal role in mammalian nociception, is activated under stressful conditions and can be an important signaling pathway for immune modulation. The endocannabinoid system could therefore be involved in the complex pathophysiology of FM. We tested this hypothesis by evaluating the effects of stress hormones and the endocannabinoid anandamide on neutrophil function in patients with FM. We determined plasma levels of catecholamines, cortisol and anandamide in 22 patients with primary FM and 22 age- and sex-matched healthy controls. Neutrophil function was characterized by measuring the hydrogen peroxide (H2O2) release (oxidative stress) and the ingestion capabilities of neutrophils (microbicidal function). FM patients had significantly higher norepinephrine and anandamide plasma levels. Neutrophils of FM patients showed an elevated spontaneous H2O2 production. The ability of neutrophils to adhere was negatively correlated with serum cortisol levels. Adhesion and phagocytosis capabilities of neutrophils correlated positively with anandamide plasma levels. In conclusion, patients with FM might benefit from pharmacologic manipulation of endocannabinoid signaling which should be tested in controlled studies.

Lymphocyte subsets and the role of TH1/TH2 balance in stressed chronic pain patients.

Background: The complex regional pain syndrome (CRPS) and fibromyalgia (FM) are chronic pain syndromes occurring in highly stressed individuals. Despite the known connection between the nervous system and immune cells, information on distribution of lymphocyte subsets under stress and pain conditions is limited. Methods: We performed a comparative study in 15 patients with CRPS type I, 22 patients with FM and 37 age- and sex-matched healthy controls and investigated the influence of pain and stress on lymphocyte number, subpopulations and the Th1/Th2 cytokine ratio in T lymphocytes. Results: Lymphocyte numbers did not differ between groups. Quantitative analyses of lymphocyte subpopulations showed a significant reduction of cytotoxic CD8+ lymphocytes in both CRPS (p < 0.01) and FM (p < 0.05) patients as compared with healthy controls. Additionally, CRPS patients were characterized by a lower percentage of IL-2-producing T cell subpopulations reflecting a diminished Th1 response in contrast to no changes in the Th2 cytokine profile. Conclusions: Future studies are warranted to answer whether such immunological changes play a pathogenetic role in CRPS and FM or merely reflect the consequences of a pain-induced neurohumoral stress response, and whether they contribute to immunosuppression in stressed chronic pain patients.

Complex Interaction of Sensory and Motor Signs and Symptoms in Chronic CRPS

Spontaneous pain, hyperalgesia as well as sensory abnormalities, autonomic, trophic, and motor disturbances are key features of Complex Regional Pain Syndrome (CRPS). This study was conceived to comprehensively characterize the interaction of these symptoms in 118 patients with chronic upper limb CRPS (duration of disease: 43±23 months). Disease-related stress, depression, and the degree of accompanying motor disability were likewise assessed. Stress and depression were measured by Posttraumatic Stress Symptoms Score and Center for Epidemiological Studies Depression Test. Motor disability of the affected hand was determined by Sequential Occupational Dexterity Assessment and Michigan Hand Questionnaire. Sensory changes were assessed by Quantitative Sensory Testing according to the standards of the German Research Network on Neuropathic Pain. Almost two-thirds of all patients exhibited spontaneous pain at rest. Hand force as well as hand motor function were found to be substantially impaired. Results of Quantitative Sensory Testing revealed a distinct pattern of generalized bilateral sensory loss and hyperalgesia, most prominently to blunt pressure. Patients reported substantial motor complaints confirmed by the objective motor disability testings. Interestingly, patients displayed clinically relevant levels of stress and depression. We conclude that chronic CRPS is characterized by a combination of ongoing pain, pain-related disability, stress and depression, potentially triggered by peripheral nerve/tissue damage and ensuing sensory loss. In order to consolidate the different dimensions of disturbances in chronic CRPS, we developed a model based on interaction analysis suggesting a complex hierarchical interaction of peripheral (injury/sensory loss) and central factors (pain/disability/stress/depression) predicting motor dysfunction and hyperalgesia.

Activation of kappa opioid receptors decreases synaptic transmission and inhibits long-term potentiation in the basolateral amygdala of the mouse.

Background: The amygdala plays an important role in the processing of chronic pain and pain memory formation. Particularly, it is involved in the emotional and affective components of the pain circuitry. The role of kappa opioid receptors in these pain conditions is only partly known. The present study investigates the effect of kappa receptor activation on synaptic transmission and synaptic plasticity in the amygdala.

Kontinuierliche Periduralanalgesie versus patientenkontrollierte intravenöse Analgesie

ZusammenfassungIn einer prospektiven, randomisierten Studie wurden die beiden klinisch etablierten, postoperativen Analgesieverfahren, die kontinuierliche thorakale Periduralanalgesie (PDA) mit Lokalanästhetikum und Fentanyl und die intravenöse patientenkontrollierte Analgesie (PCA) mit Piritramid, verglichen. Bei 50 Patienten (PDA-Gruppe n=25, PCA-Gruppe n=25), die sich einer Thorakotomie unterziehen mußten, wurden Analgesie, unerwünschte Wirkungen, Allgemeinbefindlichkeit, Krankenhausaufenthaltsdauer und Komplikationen unter den jeweiligen Verfahren untersucht. Die Ergebnisse zeigen, daß sowohl die PDA als auch die PCA zur Schmerztherapie nach Thorakotomien effektiv und sicher sind. Dennoch wurde unter PDA eine signifikant bessere analgetische Wirkung sowie eine deutlich geringere Inzidenz der unerwünschten Wirkungen Sedierung und Übelkeit erzielt. Über Juckreiz klagten die Patienten mit PDA hingegen öfter. Im Hinblick auf Lungenfunktionsparameter, die subjektive Allgemeinbefindlichkeit der Patienten und die Krankenhausaufenthaltsdauer schnitt die PDA-Gruppe ebenso tendenziell besser ab. Auch die Beurteilung des jeweiligen Analgesieverfahrens durch die Patienten fiel bei insgesamt guter Bewertung beider Verfahren in der PDA-Gruppe besser aus. Trotz dieser Vorteile führte die PDA gegenüber der PCA jedoch nicht zu einer Senkung der pulmonalen Komplikationsrate.AbstractObjectives: Continuous epidural analgesia (EA) and patient-controlled intravenous analgesia (PCA) are widely used for postoperative pain control. Studies indicate that both analgesic regimens provide good analgesia after major surgery. However, because of the following reasons it is still unclear whether one of the two modes of application is superior. First, there are conflicting data regarding the differences in pain relief and drug use between epidural and intravenous administration of opioids. Second, in many studies epidural analgesia is performed by a combination of local anaesthetics and opioids. Third, reduced morbidity was observed only in some of the studies, in which epidural analgesia provided better pain relief than systemic opioid supply. Despite these conflicting results, EA with local anaesthetics and fentanyl as well as PCA with piritramid, a highly potent μ-agonist, are routinely used in Germany. The purpose of this study was to compare these two treatments for analgesic efficacy, pulmonary function, incidence of side effects and complications in patients undergoing thoracotomy. Methods: In this prospective randomized trial 50 patients were included. For postoperative pain control 25 patients (EA group) received thoracic epidural infusion of local anaesthetics (bupivacaine 0.125% or ropivacaine 0,2%) and fentanyl 4,5µg/ml with a flow rate of 4-10 ml/h. 25 patients received intravenous PCA with piritramid (bolus 2,5 mg, lock out 15 minutes, maximum of 25 mg/4 h, no background infusion). Results: Analgesia at rest and while coughing, as evaluated by visual analogue scale, was significantly better in the EA group. EA also resulted in superior values of pulmonary function tests, general condition and a lower incidence of sedation and nausea. In contrast, patients with EA reported distinctly more pruritus than patients with PCA. Duration of hospital stay was shorter in the EA group, but this difference did not reach statistical significance. There was one atelectasis in the EA group. No major complications related to EA or PCA were observed. Conclusion: In this study EA with local anaesthetics and fentanyl provided superior postoperative pain control and a lower incidence of sedation and nausea compared to intravenous PCA with piritramid, but there was no superiority as to pulmonary complications and duration of hospital stay.

[Continuous peridural analgesia vs patient - controlled intravenous analgesia for pain therapy after thoracotomy].

ZusammenfassungIn einer prospektiven, randomisierten Studie wurden die beiden klinisch etablierten, postoperativen Analgesieverfahren, die kontinuierliche thorakale Periduralanalgesie (PDA) mit Lokalanästhetikum und Fentanyl und die intravenöse patientenkontrollierte Analgesie (PCA) mit Piritramid, verglichen. Bei 50 Patienten (PDA-Gruppe n=25, PCA-Gruppe n=25), die sich einer Thorakotomie unterziehen mußten, wurden Analgesie, unerwünschte Wirkungen, Allgemeinbefindlichkeit, Krankenhausaufenthaltsdauer und Komplikationen unter den jeweiligen Verfahren untersucht. Die Ergebnisse zeigen, daß sowohl die PDA als auch die PCA zur Schmerztherapie nach Thorakotomien effektiv und sicher sind. Dennoch wurde unter PDA eine signifikant bessere analgetische Wirkung sowie eine deutlich geringere Inzidenz der unerwünschten Wirkungen Sedierung und Übelkeit erzielt. Über Juckreiz klagten die Patienten mit PDA hingegen öfter. Im Hinblick auf Lungenfunktionsparameter, die subjektive Allgemeinbefindlichkeit der Patienten und die Krankenhausaufenthaltsdauer schnitt die PDA-Gruppe ebenso tendenziell besser ab. Auch die Beurteilung des jeweiligen Analgesieverfahrens durch die Patienten fiel bei insgesamt guter Bewertung beider Verfahren in der PDA-Gruppe besser aus. Trotz dieser Vorteile führte die PDA gegenüber der PCA jedoch nicht zu einer Senkung der pulmonalen Komplikationsrate.AbstractObjectives: Continuous epidural analgesia (EA) and patient-controlled intravenous analgesia (PCA) are widely used for postoperative pain control. Studies indicate that both analgesic regimens provide good analgesia after major surgery. However, because of the following reasons it is still unclear whether one of the two modes of application is superior. First, there are conflicting data regarding the differences in pain relief and drug use between epidural and intravenous administration of opioids. Second, in many studies epidural analgesia is performed by a combination of local anaesthetics and opioids. Third, reduced morbidity was observed only in some of the studies, in which epidural analgesia provided better pain relief than systemic opioid supply. Despite these conflicting results, EA with local anaesthetics and fentanyl as well as PCA with piritramid, a highly potent μ-agonist, are routinely used in Germany. The purpose of this study was to compare these two treatments for analgesic efficacy, pulmonary function, incidence of side effects and complications in patients undergoing thoracotomy. Methods: In this prospective randomized trial 50 patients were included. For postoperative pain control 25 patients (EA group) received thoracic epidural infusion of local anaesthetics (bupivacaine 0.125% or ropivacaine 0,2%) and fentanyl 4,5µg/ml with a flow rate of 4-10 ml/h. 25 patients received intravenous PCA with piritramid (bolus 2,5 mg, lock out 15 minutes, maximum of 25 mg/4 h, no background infusion). Results: Analgesia at rest and while coughing, as evaluated by visual analogue scale, was significantly better in the EA group. EA also resulted in superior values of pulmonary function tests, general condition and a lower incidence of sedation and nausea. In contrast, patients with EA reported distinctly more pruritus than patients with PCA. Duration of hospital stay was shorter in the EA group, but this difference did not reach statistical significance. There was one atelectasis in the EA group. No major complications related to EA or PCA were observed. Conclusion: In this study EA with local anaesthetics and fentanyl provided superior postoperative pain control and a lower incidence of sedation and nausea compared to intravenous PCA with piritramid, but there was no superiority as to pulmonary complications and duration of hospital stay.

Membrane-bound glucocorticoid receptors on distinct nociceptive neurons as potential targets for pain control through rapid non-genomic effects

Glucocorticoids were long believed to primarily function through cytosolic glucocorticoid receptor (GR) activation and subsequent classical genomic pathways. Recently, however, evidence has emerged that suggests the presence of rapid non-genomic GR-dependent signaling pathways within the brain, though their existence in spinal and peripheral nociceptive neurons remains elusive. In this paper, we aim to systemically identify GR within the spinal cord and periphery, to verify their putative membrane location and to characterize possible G protein coupling and pain modulating properties. Double immunofluorescence confocal microscopy revealed that GR predominantly localized in peripheral peptidergic and non-peptidergic nociceptive C- and Aδ-neurons and existed only marginally in myelinated mechanoreceptive and proprioreceptive neurons. Within the spinal cord, GR predominantly localized in incoming presynaptic nociceptive neurons, in pre- and postsynaptic structures of the dorsal horn, as well as in microglia. GR saturation binding revealed that these receptors are linked to the cell membrane of sensory neurons and, upon activation, they trigger membrane targeted [35S]GTPγS binding, indicating G protein coupling to a putative receptor. Importantly, subcutaneous dexamethasone immediately and dose-dependently attenuated acute nociceptive behavior elicited in an animal model of formalin-induced pain hypersensitivity compared to naive rats. Overall, this study provides firm evidence for a novel neuronal mechanism of GR agonists that is rapid, non-genomic, dependent on membrane binding and G protein coupling, and acutely modulates nociceptive behavior, thus unraveling a yet unconsidered mechanism of pain relief.