Are you better? A multi-centre study of patient-defined recovery from Complex Regional Pain Syndrome.

BACKGROUND: Complex Regional Pain Syndrome (CRPS) symptoms can significantly differ between patients, fluctuate over time, disappear or persist. This leads to problems in defining recovery and in evaluating the efficacy of therapeutic interventions. OBJECTIVES: To define recovery from the patients' perspective and better understand their priorities for treatment approaches. METHODS: Establishing an international consortium, we used a 2-Round Delphi-based study in eight countries across Europe and North America. Participants ≥18 years who met, or had met, Budapest clinical criteria were included. Round 1 participants completed the statement: 'I would/do consider myself recovered from CRPS if/because…' alongside demographic and health questionnaires. Data were thematically organised and represented as 62 statements, from which participants identified and ranked their recovery priorities in Round 2. RESULTS: Round 1 (N = 347, 80% female, 91% non-recovered) dominant ICF themes were: activities of daily living; bodily functions; external factors; participation and personal factors. The top five priority statements in Round 2 (N = 252) were: no longer having (1) CRPS-related pain, (2) generalised pain and discomfort, (3) restricted range of movement, (4) need for medication, (5) stiffness in the affected limb. With very few exceptions, priorities were consistent, irrespective of patient demographics/geography. Symptoms affecting daily activities were among those most frequently reported. CONCLUSIONS: Our data showed a small number of themes are of highest importance to CRPS patients' definition of recovery. Patients want their pain, movement restriction and reliance on medication to be addressed, above all other factors. These factors should therefore be foremost concerns for future treatment and rehabilitation programmes. SIGNIFICANCE: Those with longstanding CRPS may no longer meet diagnostic criteria but still be symptomatic. Defining recovery is therefore problematic in CRPS. Our study has identified patients' definition of recovery from CRPS, in order of priority, as relief from: their CRPS-related pain, generalised pain, movement restriction, reliance on medication, and stiffness.

Increased prevalence of posttraumatic stress disorder in CRPS.

BACKGROUND: Although specific psychological disorders in complex regional pain syndrome (CRPS) have not been identified, studies suggest that CRPS patients may have increased rates of traumatic life events. Because these events do not always lead to apparent psychological symptoms, we systematically screened CRPS patients for posttraumatic stress disorder (PTSD) to determine if PTSD could be a risk factor for CRPS. METHODS: Consecutive CRPS patients referred to two university hospital centres (University of Erlangen, UMC Mainz) between December 2011 and April 2013 were prospectively examined using a diagnostic PTSD instrument (Post-traumatic Stress Diagnostic Scale (PDS). We also tested maladaptive coping strategies (brief-COPE inventory) and the PDS severity score as predictors for CRPS. Patients with non-CRPS extremity pain and healthy individuals were used as control groups. RESULTS: We collected data from 152 patients with CRPS, 55 control patients and 55 age- and sex-matched healthy individuals. Fifty-eight CRPS patients (38%), six non-CRPS pain patients (10%) and two healthy individuals (4%) met diagnostic criteria for PTSD. Initial PTSD symptom onset was prior to CRPS in 50 CRPS patients (86%) and during the course of CRPS in eight patients. Results of a logistic regression revealed that the PTSD severity score was associated with CRPS (p < 0.0001). Maladaptive coping strategies (p < 0.0001) were related to PTSD. CONCLUSIONS: posttraumatic stress disorder (PTSD) is more frequent in patients with CRPS than it is in the general population. SIGNIFICANCE: Research has not yet provided support for specific psychological predictors for CRPS.

Association between pain, central sensitization and anxiety in postherpetic neuralgia.

BACKGROUND: In postherpetic neuralgia (PHN), dorsal root ganglia neurons are damaged. According to the proposed models, PHN pain might be associated with nociceptive deafferentation, and peripheral (heat hyperalgesia) or central sensitization (allodynia). METHODS: In 36 PHN patients, afferent nerve fibre function was characterized using quantitative sensory testing and histamine-induced flare analysis. Psychological factors were evaluated with the Hospital Anxiety and Depression Scale (HADS), disease-related quality of life (QoL) with SF-36 and pain with the McGill questionnaire [pain rating index (PRI)]. The patients were also divided into subgroups according to the presence or absence of brush-evoked allodynia as a sign of central sensitization. RESULTS: For all patients, warm, cold and mechanical detection was impaired (p < 0.001 each) and the size of the histamine flare was diminished on the affected side (p < 0.05); pain thresholds with the exception of brush-evoked allodynia (p < 0.05) were unaltered. Correlation analysis revealed allodynia, anxiety, depression, QoL and age as relevant factors associated with pain severity (PRI). Allodynia was present in 23 patients (64%). In these patients, heat pain perception was preserved; the histamine flare was larger; the pinprick pain was increased as were McGill PRI sensory subscore, actual pain rating and almost significantly pain (McGill PRI) over the last 4 weeks. CONCLUSIONS: PHN is associated with damage of afferent fibres. Central sensitization (i.e., allodynia) might contribute to PHN pain. There was a striking association between anxiety, depression and age, and the magnitude of PHN pain.

[Current aspects of the therapy of complex regional pain syndrome]. / Aktuelles zur Therapie des komplex-regionalen Schmerzsyndroms.

BACKGROUND: Complex regional pain syndrome (CRPS) constitutes an enigmatic post-traumatic pain disorder. AIM OF THE STUDY: The paper provides state of the art knowledge about CRPS. RESULTS: The typical constellation of symptoms of CRPS includes pain, sensory disturbances, motor symptoms, disturbances of the autonomic control of the limbs and trophic changes. These symptoms generalize distally and go beyond single nerve innervation territories. Diagnosis is made based on clinical findings. Three-phase bone scintigraphy may be the best supporting technical investigation. Symptoms typically change during the course of CRPS. In the acute stage inflammatory symptoms prevail and during chronic stages the most expressed findings are related to central neuroplasticity. These findings include hyperalgesia, sensory loss, CRPS movement disorder, body perception disturbances and autonomic symptoms. Medical treatment with anti-inflammatory agents (steroids) or bisphosphonates is most effective in the early stages and DMSO cream might also be beneficial. Administration of i.v. ketamine has been proven effective against CRPS pain and physical therapy with behavioral components, such as pain exposure helps to overcome central reorganization and functional impairment. Psychotherapy should be offered if there are significant comorbidities. All other forms of treatment are more or less empirical. Invasive treatment should be restricted to selected cases and should only be offered in specialized centers. DISCUSSION: If these recommendations are followed the prognosis for CRPS is not as poor as commonly assumed. Whether this means a return to the previous quality of life is unclear and often depends on very personal factors.

[Effect of botulinum toxin type B on residual limb sweating and pain. Is there a chance for indirect phantom pain reduction by improved prosthesis use?]. / Wirkung von Botulinumtoxin Typ B auf Stumpfschwitzen und Stumpfschmerzen. Besteht die Chance der indirekten Phantomschmerzreduktion durch bessere Prothesennutzung?

OBJECTIVES: Hyperhidrosis of a residual limb after amputation is one of the most common reasons for impaired prosthesis use and quality of life and affects 30-50% of all amputees causing skin irritation in about 25%. Thus the probability of residual limb pain increases in addition to an increased likelihood of phantom pain due to shorter duration of prothesis use. Development of both types of pain was studied following treatment of hyperhidrosis in 9 amputees. DESIGN: A total of 9 lower limb amputees received injections of 1750 units of botulinum toxin type B (BTX-B) for the treatment of hyperhidrosis of a residual limb (20 intracutaneous injections each). Prior to injections and 4 weeks and 3 months afterwards, patients rated the impairments regarding residual limb pain, phantom pain and sweating of the residual limb. Furthermore the duration of use of the prosthetic device and quality of life were rated on a numeric rating scale (NRS 0-10). RESULTS: Stump pain (n=9) was highly significantly reduced after 3 months (baseline: NRS 5; 4 weeks: NRS 4, p=0.109; 3 months: NRS 3, p=0.008) and also a tendency for phantom pain after 3 months (baseline NRS 5; 3 months: NRS 3; p=0.109). Sweating of the residual limb prior to BTX-B application was rated as a median 7 on the NRS scale with significant improvements after 4 weeks (NRS 3, p=0.027) and 3 months (NRS 3, p=0.020). Impaired duration of prothesis use improved from NRS 8 to NRS 2 (4 weeks; p=0.023) and NRS 3 (3 months; p=0.023) as well as the quality of life (p=0.016, p=0.023, respectively). CONCLUSIONS: Residual limb pain improved 3 months after intracutaneous, low-dose BTX-B in a trial with 9 patients and also phantom pain by tendency. Sweating of the residual limb was significantly reduced, probably thereby improving the duration of prothesis use. Larger studies should confirm these findings and conclusions.

Naloxone inhibits not only stress-induced analgesia but also sympathetic activation and baroreceptor-reflex sensitivity.

Interactions between the sympathetic nervous system and pain are manifold and still have not been sufficiently characterized. Accordingly, several possible neuronal pathways have been described as being involved in mental stress-induced analgesia. We studied the role of the endogenous opioidergic system in stress-induced analgesia in 14 healthy participants in a double-blind cross-over trial. Naloxone or placebo was applied while electrical pain stimulation was started and electrical current increased. After reaching a constant stimulation at 30 mA, a color word interference test (Stroop task) was performed in a stressful and a non-stressful version. Blood pressure, heart rate and baroreflex sensitivity were continuously recorded to assess autonomic activation. Each participant was tested with naloxone and placebo with a randomized and balanced order of trials. The major results are that the opioid-receptor antagonist naloxone prevented (1) stress-induced reduction of tonic current-induced pain, (2) attenuated the simultaneous activation of the sympathetic nervous system, and (3) reduced the counteraction of sympathetic activation by vagal baroreceptor mechanisms. Thus, the opioidergic system not only modulates nociceptive input but also the interplay with vegetative responses. We conclude that acute stress, sympathetic activation and analgesia might be linked via vagal reflexes, which are disturbed when opioid receptors are blocked. This mechanism might underlie increased perception of noxious stimuli in patients with chronic pain or mood disorders.

Application of local anesthesia inhibits effects of low-energy extracorporeal shock wave treatment (ESWT) on nociceptors.

OBJECTIVE: Clinical studies of extracorporeal shock wave therapy (ESWT) provided conflicting results depending on the use of local anesthesia (LA). DESIGN: The present study investigated whether the biological effects of ESWT differ between application with and without LA. SETTING AND PATIENTS: In 20 healthy subjects, ESWT was applied to the ventral surface of forearm skin, either after topical lidocaine pretreatment or without on the corresponding contralateral side. MEASURES: During and after ESWT ongoing pain, axon-reflex vasodilation (laser Doppler imaging), thresholds for pinprick, and blunt pressure were recorded. RESULTS: The results indicate that increasing ESWT energy flux density led to increasing pain (P < 0.001). LA reduced ESWT-related pain (P < 0.02) and in parallel inhibited local axon-reflex vasodilation (P < 0.001). In addition, LA prevented ESWT-related drop in pressure pain threshold (P < 0.001). CONCLUSION: This study provided evidence that ESWT dose-dependently activates and sensitizes primary afferent nociceptive C-fibers, and that both activation and sensitization were prevented if LA was applied locally. These results suggest that LA substantially alters the biological responses of ESWT.

Highly anisotropic decay rates of single quantum dots in photonic crystal membranes.

We have measured the variation of the spontaneous emission rate with polarization for self-assembled single quantum dots in two-dimensional photonic crystal membranes. We observe a maximum anisotropy factor of 6 between the decay rates of the two bright exciton states. This large anisotropy is attributed to the substantially different projected local density of optical states for differently oriented dipoles in the photonic crystal.

Cortical control of thermoregulatory sympathetic activation.

Thermoregulation enables adaptation to different ambient temperatures. A complex network of central autonomic centres may be involved. In contrast to the brainstem, the role of the cortex has not been clearly evaluated. This study was therefore designed to address cerebral function during a whole thermoregulatory cycle (cold, neutral and warm stimulation) using 18-fluordeoxyglucose-PET (FDG-PET). Sympathetic activation parameters were co-registered. Ten healthy male volunteers were examined three times on three different days in a water-perfused whole-body suit. After a baseline period (32 degrees C), temperature was either decreased to 7 degrees C (cold), increased to 50 degrees C (warm) or kept constant (32 degrees C, neutral), thereafter the PET examination was performed. Cerebral glucose metabolism was increased in infrapontine brainstem and cerebellar hemispheres during cooling and warming, each compared with neutral temperature. Simultaneously, FDG uptake decreased in the bilateral anterior/mid-cingulate cortex during warming, and in the right insula during cooling and warming. Conjunction analyses revealed that right insular deactivation and brainstem activation appeared both during cold and warm stimulation. Metabolic connectivity analyses revealed positive correlations between the cortical activations, and negative correlations between these cortical areas and brainstem/cerebellar regions. Heart rate changes negatively correlated with glucose metabolism in the anterior cingulate cortex and in the middle frontal gyrus/dorsolateral prefrontal cortex, and changes of sweating with glucose metabolism in the posterior cingulate cortex. In summary, these results suggest that the cerebral cortex exerts an inhibitory control on autonomic centres located in the brainstem or cerebellum. These findings may represent reasonable explanations for sympathetic hyperactivity, which occurs, for example, after hemispheric stroke.

Functional imaging of sympathetic activation during mental stress.

Activation of the sympathetic nervous system (SNS) is essential in adapting to environmental stressors and in maintaining homeostasis. This reaction can also turn into maladaptation, associated with a wide spectrum of stress-related diseases. Up to now, the cortical mechanisms of sympathetic activation in acute mental stress have not been sufficiently characterized. We therefore investigated cerebral activation applying functional magnetic resonance imaging (fMRI) during performance of a mental stress task with graded levels of difficulty, i.e. four versions of a Stroop task (Colour Word Interference Test, CWT) in healthy subjects. To analyze stress-associated sympathetic activation, skin conductance and heart rate were continuously recorded. The results show that sympathetic activation through mental stress is associated with distinct cerebral regions being immediately involved in task performance (visual, motor, and premotor areas). Other activated regions (right insula, dorsolateral superior frontal gyrus, cerebellar regions) are unrelated to task performance. These latter regions have previously been considered to be involved in mediating different stress responses. The results might furthermore serve as a basis for future investigations of the connection between these cortical regions in the generation of stress-related diseases.

Stress and thermoregulation: different sympathetic responses and different effects on experimental pain.

Stress and thermoregulation both activate the sympathetic nervous system (SNS) but might differently affect pain. Studies investigating possible interactions in patients are problematic because of the high prevalence of SNS disturbances in patients. We therefore analyzed the influence of these different sympathetic challenges on experimentally-induced pain in healthy subjects. SNS was activated in two different ways: by mental stress (Stroop task, mental arithmetic task), and by thermoregulatory stimulation using a water-perfused thermal suit (7 degrees C, 32 degrees C, or 50 degrees C). Attentional effects of the mental stress tasks were controlled by using easy control tasks. Both, stress and thermoregulatory stimuli, robustly activated SNS parameters. However, the patterns of activation were different. While stress co-activated heart rate, blood pressure, peripheral vasoconstriction and sweating, thermal stimulation either increased blood pressure (cold) or heart rate and sweating (warm). Only stress was able to induce a significant reduction of pain. The control tasks neither activated the SNS nor altered pain perception. Our results suggest that (1) different patterns of sympathetic activation can be recorded after stress and thermoregulatory challenges and (2) that only stress is able to interfere with sensation of experimental pain. Whether SNS activation is causally responsible for analgesia needs to be further investigated.

Patterns of sympathetic responses induced by different stress tasks.

Stress tasks are used to induce sympathetic nervous system (SNS) arousal. However, the efficacy and the patterns of SNS activation have not been systematically compared between different tasks. Therefore, we analyzed SNS activation during the following stress tasks: Presentation of negative, positive, and - as a control - neutral affective pictures, Color-Word interference test (CWT), mental arithmetic under time limit, singing a song aloud, and giving a spontaneous talk. We examined 11 healthy subjects and recorded the following SNS parameters: Activation of emotional sweating by quantitative sudometry, skin vasoconstriction by laser-Doppler flowmetry, heart rate by ECG, blood pressure by determination of pulse wave transit time (PWTT), and electromyographic (EMG) activity of the trapezius muscle. Moreover, subjective stress ratings were acquired for each task using a visual analog scale. All tasks were felt significantly stressful when compared to viewing neutral pictures. However, SNS activation was not reliable: Affective pictures did not induce a significant SNS response; singing, giving a talk and mental arithmetic selectively increased heart rate and emotional sweating. Only the CWT globally activated the SNS. Regarding all tasks, induction of emotional sweating, increase of heart rate and blood pressure significantly correlated with subjective stress ratings, in contrast to EMG and skin vasoconstriction.Our results show that the activation of the SNS widely varies depending on the stress task. Different stress tasks differently activate the SNS, which is an important finding when considering sympathetic reactions - in clinical situations and in research.

Tailoring of morphology and emission wavelength of AlGaInAs quantum dots.

We present a study of the growth, morphology and optical properties of Al(x)Ga(1-x-y)In(y)As quantum dots (QDs) for a wide range of Al and In concentrations (0≤x≤0.34 and 0.43≤y≤0.60). Short emission wavelengths between 660 and 940 nm and QD surface densities up to 1.1 × 10(11) cm(-2) have been achieved. Our results show that by varying both the Al concentration and the In concentration an independent adjustment of strain and QD band gap is possible. This additional degree of freedom can be employed for tailoring AlGaInAs QDs with the desired emission wavelength, surface density and average size. AlGaInAs QDs thus offer new possibilities for future QD device design.

Adsorption and reaction of SO2 with a polycrystalline UO2 film: promotion of S-O bond cleavage by creation of O-defects and Na or Ca coadsorption.

To characterize UO(2) for its possible use in desulfurization applications, the interactions of molecular sulfur dioxide (SO(2)) with a polycrystalline uranium dioxide film have been studied by means of X-ray photoelectron spectroscopy (XPS), temperature-programmed desorption (TPD), and low-energy ion scattering (LEIS). The stoichiometric, oxygen-deficient, calcium-precovered and sodium-precovered UO(2) surfaces have been characterized. The changes in oxide reactivity upon creation of oxygen vacancies and coadsorption of sodium and calcium have been studied. After creation of a reduced UO(2-x) surface (x approximately 0.44) via Ar(+) sputtering, the U 4f XPS spectrum shows conspicuous differences that are good indicators of the surface stoichiometry. Molecular SO(x) formation (x = 2-4) is observed after SO(2) deposition onto stoichiometric UO(2) and onto UO(2) precovered with small amounts (<1 ML) of Na or Ca; complete dissociation of SO(2) is not observed. Heating leads to desorption of the SO(x) species and to transformation of SO(2) to SO(3) and SO(3) to SO(4). On oxygen-deficient UO(2) and on UO(2) precovered with large Na or Ca coverages (> or =4 ML), both the formation of SO(x)= species and complete dissociation of SO(2) are observed. A higher thermal stability of the sulfur components is observed on these surfaces. In all cases for which dissociation occurs, the XPS peak of atomic sulfur shows similar structure: three different binding states are observed. The reactivity of oxygen-deficient UO(2) and sodium- and calcium-precovered UO(2) (coverages > or = 4 ML) is attributed to charge transfer into the antibonding LUMO of the adsorbed molecule.

Spatial discrimination thresholds for pain and touch in human hairy skin.

The traditional concept that pain is poorly localized has been challenged by recent studies, where subjects were able to point to the stimulated spot on the skin with an accuracy of 10-20 mm. Pointing movements themselves, however, have errors of about 15 mm. To determine the limits of sensory performance of the nociceptive system independent of motor performance, point localization of heat pain (540 mJ punctate laser stimuli, 5 mm diameter), mechanical pain (256 mN punctate probe, 200 microm diameter), and touch (16 mN von Frey probe, 1.1 mm diameter) were tested in a two-alternative forced-choice paradigm in 12 healthy subjects. Stimuli were applied in randomized order to two parallel lines on the back of the hand (4-32 mm distance). The cumulative distribution functions for correct localization were of similar sigmoid shape for all test stimuli, indicating logarithmic normal distributions. The 75% correct localization threshold for painful heat was 8.6 mm (3.1 +/- 0.1 log2 units) and did not differ significantly from that of non-painful touch (9.0 mm, 3.2+/-0.2 log2 units). Localization of mechanically-induced pain (5.1 mm, 2.4 +/- 0.2 log2 units) was significantly more accurate than both heat pain and touch, possibly due to a synergism of two different sensory channels, the tactile channel and the nociceptive channel, which were activated simultaneously. For all three stimuli, discrimination was significantly better in radial-ulnar compared to proximal-distal direction, which might be related to oval receptive field shapes. Sequential spatial discrimination for touch was significantly better than simultaneous spatial discrimination tested with a grating orientation task (18.9 mm), but both were one order of magnitude worse than at the finger tip (1.3 mm, 0.4 +/- 0.1 log2 units). In conclusion, pain evoked by radiant heat pulses and touch evoked by von Frey probes were localized with similar precision on the back of the hand. These findings indicate that outside the tactile fovea at finger tips or lips the spatial discrimination capacities of the nociceptive and tactile systems are about equal.