Traumatic Events, Posttraumatic Stress Disorder, and Central Sensitization in Chronic Pain Patients of a German University Outpatient Pain Clinic.

OBJECTIVE: Posttraumatic stress disorder (PTSD) and traumatic life events are often coupled to chronic pain, possibly linked by central sensitization. We wanted to assess the prevalence of traumatic events and PTSD in chronic pain patients of a German university hospital outpatient pain clinic. Moreover, we evaluated the extent of indicators and co-occurring traits of central sensitization in comorbid patients. METHODS: We retrospectively divided 914 chronic pain patients into four groups depending on their trauma severity: no trauma, accidental trauma, interpersonal trauma, and PTSD. We collected electronic pain drawings focusing on pain area and widespreadness, as well as information about pain intensity, sleep impairment, disability, stress, anxiety, depression, and somatization. Differences between groups were calculated using Kruskal-Wallis with post-hoc Mann-Whitney tests. RESULTS: Of 914 patients, 231 (25%) had no trauma, 210 (23%) had accidental traumas, 283 (31%) had interpersonal traumas, 99 (11%) had PTSD, and 91 (10%) could not be classified. We observed statistically significant differences between groups in pain area and widespreadness, as well as maximal pain, sleep impairment, disability, stress, anxiety, depression, and somatization. The severity of symptoms increased with trauma severity. CONCLUSIONS: Traumatic life events and PTSD are frequent in chronic pain patients. The increased pain area and widespreadness, as well as the increased negative impact on co-occurring traits of sensory sensitivity (anxiety, depression, somatization), are compatible with central sensitization in comorbid patients. Therefore, a heightened awareness of the comorbidity between traumatic experiences and chronic pain is recommended.

[Project report on fostering scientific competencies in pain medicine in the context of student education]. / Projektbericht zur Förderung wissenschaftlicher Kompetenzen im Fach Schmerzmedizin im Rahmen der curricularen Lehre.

AIM: The training of scientific skills and competencies is an essential part of academic medical studies. As part of the MaReCuM model study program at Heidelberg University's Mannheim Medical School, a fifth-year rotation on scientific skills in the field of pain medicine was implemented. This paper describes this competence-oriented rotation as well as the investigation of the educational effect. METHOD: A total of 114 fifth-year medical students participated in the survey (response rate: 83%). The control group completed the fifth year prior to the implementation of the rotation. The experimental group was required to participate in the rotation and the real healthcare research study "Case management program: low back pain". A survey of both groups was conducted on the first day of the rotation and at the end of the module. RESULTS: The innovative and competency-based learning unit was successfully implemented as part of the MaReCuM model study program and carried out with partners in general practice as well as the Mannheim Institute of Public Health. The participating students accepted the rotation well. There was no measurable effect on the subjective learning success of the rotation in the evaluation. DISCUSSION: To the authors' knowledge, this educational approach has never been tested before in a German study program. The presented rotation offers an additional option for the training of scientific competencies as part of medical studies. The missing of a measurable effect could be due to the extensive experience of the medical students as well as the limitations on participation in a real healthcare study. An additional learning opportunity could be created by connecting the preexisting lectures to a longitudinal module on scholarly competencies. The implementation of the program also offers a unique opportunity for educational research on the acquisition of scientific competencies in medical students.

[Perioperative Pain Management - Patient Information, Informed Consent and Discharge Management]. / Anästhesiologisches Management der perioperativen Schmerztherapie.

Many surgical procedures are followed by postoperative pain. Acute pain should be treated optimally for medical and ethical reasons. Different psychological, physical, interventional and pharmacological methods are employed in a procedure specific and institution specific matter. For optimum patient care, implementation of acute pain management concepts in recommendations on quality management in German hospitals and outpatient clinics was enacted in September 2020 by Gemeinsamer Bundessausschuss (G-BA). Implementation of discharge management had already been enacted in 2017 for structured prescription of medication after hospital discharge, among other things. On the other hand, new national and international developments require a new weighting of pharmacotherapy in particular. Examples include debates on the safe use of metamizol and the opioid crisis in the US. To address these issues adjustments in informed consent and patient information and education are necessary. This includes also the information and education of caregivers. This article describes the legal framework, technical solutions and the impact of placebo and nocebo effects on doctor-patient communication.

Figure Correction: Digital Pain Drawings Can Improve Doctors' Understanding of Acute Pain Patients: Survey and Pain Drawing Analysis.

[This corrects the article DOI: 10.2196/11412.].

Digital Pain Drawings Can Improve Doctors' Understanding of Acute Pain Patients: Survey and Pain Drawing Analysis.

BACKGROUND: Pain drawings (PDs) are an important tool to evaluate, communicate, and objectify pain. In the past few years, there has been a shift toward tablet-based acquisition of PDs, and several studies have been conducted to test the usefulness, reliability, and repeatability of electronic PDs. However, to our knowledge, no study has investigated the potential role of electronic PDs in the clinical assessment and treatment of inpatients in acute pain situations. OBJECTIVE: The aim of this study was to evaluate whether knowledge of the patients' electronic PD has the potential to improve the doctors' understanding of their patients and to influence their clinical decision making. Furthermore, we sought to identify differences between electronic PDs of patients and their treating pain specialists in an acute pain situation and to find those specific characteristics derived from the PDs that had the largest impact on doctors' understanding. METHODS: We obtained electronic PDs from 47 inpatients in acute pain situations before their consultation with a pain specialist on a tablet personal computer with a stylus. Before looking at their patients' drawings, these specialists drew their own conception of the patients' pain after anamnesis and physical examination. Patients' drawings were then revealed to the doctors, and they were asked to evaluate how much the additional information improved their understanding of the case and how much it influenced their clinical decision on an 11-point Likert scale (0="not at all" and 10="very much"). Similarities and differences of patients' and doctors' PDs were assessed by visual inspection and by calculating Jaccard index and intraclass correlation coefficient (ICC) of the pain area and the number of pain clusters. Exploratory analyses were conducted by means of correlation tables to identify specific factors that influenced doctors' understanding. RESULTS: Patients' PDs significantly improved the doctors' understanding (mean score 4.81, SD 2.60, P<.001) and to a lesser extent their clinical decision (mean 2.68, SD 1.18, P<.001). Electronic PDs of patients and doctors showed fair to good similarity for pain extent (r=.454, P=.001) and widespreadness (P=.447, r=.002) were important factors helping doctors to understand their patients. CONCLUSIONS: In a clinical setting, electronic PDs can improve doctors' understanding of patients in acute pain situations. The ability of electronic PDs to visualize differences between doctors' and patients' conception of pain has the potential to improve doctor-patient communication.

Designing a Tablet-Based Software App for Mapping Bodily Symptoms: Usability Evaluation and Reproducibility Analysis.

BACKGROUND: Symptom drawings are widely used as a qualitative and quantitative method of assessing pain symptoms for both clinical and research purposes. As electronic drawings offer many advantages over classical pen-and-paper drawings, the last years have seen a shift toward tablet-based acquisition of symptom drawings. However, software that is used in clinical care requires special attention to usability aspects and design to provide easy access for physically impaired or elderly patients. OBJECTIVE: The aims of this project were to develop a new tablet-based software app specifically designed to collect patients' and doctors' drawings of pain and related bodily symptoms and test it for usability in 2 samples of chronic pain patients (Aim 1) and their treating doctors (Aim 2) as well as for test-retest reliability (Aim 3). METHODS: In 2 separate studies, symptom drawings from 103 chronic pain patients and their treating doctors were collected using 2 different versions of the app. Both patients and doctors evaluated usability aspects of the app through questionnaires. Results from study 1 were used to improve certain features of the app, which were then evaluated in study 2. Furthermore, a subgroup of 25 patients in study 2 created 2 consecutive symptom drawings for test-retest reproducibility analysis. Usability of both app versions was compared, and reproducibility was calculated for symptom extent, number of symptom clusters, and the whole symptom pattern. RESULTS: The changes we made to the app and the body outline led to significant improvements in patients' usability evaluation regarding the identification with the body outline (P=.007) and the evaluation of symptom depth (P=.02), and the overall difficultness of the drawing process (P=.003) improved significantly. Doctors' usability evaluation of the final app showed good usability with 75.63 (SD 19.51) points on the System Usability Scale, Attrakdiff 2 scores from 0.93 to 1.41, and ISONORM 9241/10 scores from -0.05 to 1.80. Test-retest analysis showed excellent reproducibility for pain extent (intraclass correlation coefficient, ICC=0.92) and good results for the number of symptom clusters (ICC=0.70) and a mean overlap of 0.47 (Jaccard index). CONCLUSIONS: We developed a tablet-based symptom drawing app and improved it based on usability assessment in a sample of chronic pain patients and their treating doctors. Increases in usability of the improved app comprised identification with the body outline, symptom depth evaluation, and difficultness of the drawing process. Test-retest reliability of symptom drawings by chronic pain patients showed fair to excellent reproducibility. Patients' usability evaluation is an important factor that should not be neglected when designing apps for mobile or eHealth apps.

Competency-based learning in an ambulatory care setting: Implementation of simulation training in the Ambulatory Care Rotation during the final year of the MaReCuM model curriculum.

Aim: As part of the MaReCuM model curriculum at Medical Faculty Mannheim Heidelberg University, a final year rotation in ambulatory care was implemented and augmented to include ambulatory care simulation. In this paper we describe this ambulatory care simulation, the designated competency-based learning objectives, and evaluate the educational effect of the ambulatory care simulation training. Method: Seventy-five final year medical students participated in the survey (response rate: 83%). The control group completed the ambulatory rotation prior to the implementation of the ambulatory care simulation. The experimental group was required to participate in the simulation at the beginning of the final year rotation in ambulatory care. A survey of both groups was conducted at the beginning and at the end of the rotation. The learning objectives were taken from the National Competency-based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM). Results: The ambulatory care simulation had no measurable influence on students' subjectively perceived learning progress, the evaluation of the ambulatory care rotation, or working in an ambulatory care setting. At the end of the rotation participants in both groups reported having gained better insight into treating outpatients. At the beginning of the rotation members of both groups assessed their competencies to be at the same level. The simulated ambulatory scenarios were evaluated by the participating students as being well structured and easy to understand. The scenarios successfully created a sense of time pressure for those confronted with them. The ability to correctly fill out a narcotic prescription form as required was rated significantly higher by those who participated in the simulation. Participation in the ambulatory care simulation had no effect on the other competencies covered by the survey. Discussion: The effect of the four instructional units comprising the ambulatory care simulation was not measurable due to the current form or the measurement point at the end of the 12-week rotation. The reasons for this could be the many and statistically elusive factors relevant to the individual and the wide variety among final year rotation placements, the late point in time of the final survey, and the selection of simulated scenarios. The course is slated to undergo specific further development and should be supplemented with additional learning opportunities to ensure that the main learning objectives are covered. The description of the teaching format is meant to contribute to the ongoing development of medical education with an emphasis on competency in the areas of ambulatory care, communication, prevention and health promotion.

Mechano-insensitive nociceptors are sufficient to induce histamine-induced itch.

The nerve fibres underlying histamine-induced itch have not been fully elucidated. We blocked the lateral femoral cutaneous nerve and mapped the skin area unresponsive to mechanical stimulation, but still sensitive to electrically induced pain. Nerve block induced significantly larger anaesthetic areas to mechanical (100 mN pin-prick, 402 ± 61 cm²; brush, 393 ± 63 cm²) and heat pain stimuli (401 ± 53 cm²) compared with electrical stimulation (352 ± 62 cm², p < 0.05), whereas the anaesthetic area tested with 260 mN (374 ± 57 cm²) did not differ significantly. Histamine was applied by iontophoresis (7.5 mC) at skin sites in which mechanical sensitivity was blocked, but electrical stimulation was still perceived 30 min after the nerve block (n = 9). In these areas iontophoresis of histamine provoked itching in 8/9 subjects with a mean maximum of 4.6 ± 1 (on an 11-point rating scale). Histamine-induced itch can thus be perceived at skin sites where input from mechano-sensitive polymodal nociceptors is blocked. In conclusion, input from mechano-insensitive nociceptors is sufficient to generate histamine-induced itch.

Discriminative sensory characteristics of the lateral femoral cutaneous nerve after mepivacaine-induced block.

Background and objectives Unmyelinated C-fibres comprise the largest group of somatic afferents and have demonstrated a crucial role not only in the perception of high-threshold mechanically, thermally or chemically induced pain, but also in non-harmful low-threshold mechanical stimuli [1,2]. The objective of our study was to characterize differential sensitivity changes of C-fibre related subclasses of high-threshold and low-threshold polymodal nociceptors and low-threshold mechanoreceptors to the local anaesthetic (LA) mepivacaine during nerve block of the purely sensory lateral femoral cutaneous nerve (LFCN) in human. We assumed a diverse response of different classes of afferents to the two different concentrations of the LA mepivacaine (Scandicaine). Methods In a double-blind randomized experimental setting, an ultrasound-guided nerve block of the LFCN was performed in 10 healthy male subjects, each with two different concentrations of mepivacaine (0.5 and 1%). Responsiveness of afferent nerve fibres to different noxious and non-noxious stimuli was tested by Quantitative Sensory Testing (QST) 30, 180, and 300 min after nerve block. Both LA concentrations of mepivacaine were compared for time course of the areas of anaesthesia for the tested sensory modalities. Results Initial extension of anaesthetic areas at 30 min did not differ between both LA concentrations. At 180 min only the anaesthetic areas to nociceptive stimuli were reduced at the site of lower mepivacaine injection (260mN: 204mm2 (18; 244; median difference and 95% confidence interval; p < 0.05), heat: 276mm2 (3; 305)). In contrast, no significant differences were found between the two concentration when non-nociceptive stimuli were used (100mN: 187mm2 (4; 240), p >0.05, brush: 159mm2 (-59; 202)). Conclusion Equal initial sizes of anaesthesia areas for all sensory modalities can be explained by supramaximal perineural LA molecule concentration in both administered mepivacaine dosages. Upon washout of the LA nociceptive function is restored faster as compared to non-nociceptive sensation and higher concentration of the LA are required to maintain the analgesia. Quantitative sensory testing is able to detect different susceptibility of low threshold mechanosensors and subtypes of nociceptive C-fibres to mepivacaine. Using painful mechanical, heat and electrical stimulation different classes of nociceptors will be activated. The analgesic areas to electrical stimulation were particularly small; one might therefore hypothesize that the proposed protocol allows to also differentiate mechano-insensitive ("silent") and mechanosensitive ("polymodal") nociceptors. Implications QST is a non-invasive method to functionally examine sensory modalities and their pharmacological modulation in humans. The method is sufficiently sensitive to differentiate the analgesic properties of mepivacaine at 0.5 and 1% and might also be adequate to different classes of nociceptors. Further development of nociceptive stimuli including supra-threshold encoding characteristics will enable to investigate peripheral analgesic effects more specifically and thus might help to design new analgesics with preferential effect on high frequency discharge of nociceptors.

Nerve growth factor-evoked nociceptor sensitization in pig skin in vivo.

Peripheral sensitization of skin nociceptors by nerve growth factor (NGF) was explored in pig skin in vivo. As an objective output measure, the area of axon-reflex-mediated erythema was assessed upon mechanical, thermal, chemical, and electrical stimuli delivered at 1, 3, and 7 days after i.d. injection of 1 microg NGF into the pig's back skin (n = 8). Pretreatment with NGF provoked a sensitization to mechanical (600 mN), thermal (10 sec 49 degrees C) and chemical (15 microl, pH 3) stimuli that lasted for 7 days. No sensitization, however, was found in response to weak mechanical (100 mN), weak thermal (10 sec 45 degrees C), or electrical stimuli. Irrespective of the skin pretreatment (NGF or PBS vehicle control), the area of electrically induced erythema decreased upon repetition (days 1-7) by 70% (P < 0.05). Sensitization of sensory endings by NGF upon mechanical, heat, and chemical stimuli suggests recruitment of sensory transducer molecules [e.g., TRPV1, acid-sensing ion channels (ASICs)]. In contrast, the gradual decrease in electrically induced erythema over 7 days might be attributable to axonal desensitization and possibly activity-dependent down-regulation of sodium channels. Thus, long-lasting sensitization processes of nociceptor endings or axonal sodium channel desensitization mechanisms can be explored in the pig as a translational experimental animal model.

Long-acting local anesthetics attenuate FMLP-induced acute lung injury in rats.

BACKGROUND: Endothelin-1 (ET-1) is a mediator of lung diseases and a potent pulmonary vasoconstrictor. In addition to thromboxane A2, it participates in the formation of lung edema. Both lidocaine and mepivacaine attenuate the increase of pulmonary arterial pressure (PAP) and lung edema development. We examined the effects of procaine, bupivacaine, and ropivacaine on experimentally evoked PAP increase and ET-1 release. METHODS: PAP and lung weight were measured in isolated rat lungs during perfusion with Krebs-Henseleit hydroxyethyl starch buffer. Bupivacaine, ropivacaine, or procaine was added to the solution at concentrations of 10(-2)-10(-7) mg/kg. ET-1 levels were measured in the perfusate by enzyme-immunoassay, and thromboxane A2 levels were assayed by radioimmunoassay. N-formyl-L-leucine-methionyl-L-phenylalanine was used to activate human polymorphonuclear neutrophils. RESULTS: Bupivacaine, ropivacaine, and procaine significantly attenuated increases of PAP (P < 0.05) and resulted in a reduction of lung weight in these treatment groups compared with the sham group (P < 0.05). The long-acting anesthetics bupivacaine and ropivacaine (P < 0.05), but not procaine, reduced ET-1 levels, produced low inflammation rates, and did not affect lung structures at doses from 10(-3) to 10(-6) mg/kg. CONCLUSION: Bupivacaine and ropivacaine attenuated N-formyl-L-leucine-methionyl-L-phenylalanine-induced PAP, reduced lung edema, and diminished ET-1 release. Lidocaine and mepivacaine are more effective in reducing PAP and edema formation, but long-acting local anesthetics also inhibit ET-1 depletion and therefore have increased anti-inflammatory properties.

Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans.

BACKGROUND AND OBJECTIVES: The most abundant malignant brain tumor in human is glioblastoma and patients with this type of tumor have a poor prognosis with high mortality. Glioblastoma are characterized particularly by fast growth and a dependence on blood vessel formation for survival. Cannabinoids (CBs) inhibit tumor growth by inducing apoptosis of tumor cells and impairing tumor angiogenesis. The distribution of CB1 and CB2 receptors in glioblastoma and associated endothelial vessels is still unknown. METHODS: Tissue samples were collected consecutively after neurosurgery of 19 patients suspected glioblastoma and examined immunohistochemically for CB1 and CB2 receptor expression. Vessel endothelial cells of the sections were immunocytochemically identified by using a primary antibody against PECAM-1. Double labelling was performed for CB receptors and endothelial cells of the vessels by DAPI staining. RESULTS: In endothelia of control tissue, about 24% and 45% of the cells were positive for CB1 and CB2 receptors. In glioblastoma endothelial cells, CB1 and CB2 receptors were present in about 38% and 54% of the cells respectively. In comparison to CB1, an elevated CB2 receptor expression was identified in glioblastoma. CONCLUSIONS: The abundant expression and distribution of CB2 receptors in glioblastoma and particularly endothelial cells of glioblastoma indicate that impaired tumor growth in presence of CB may be associated with CB2 activation. Selective CB2 agonists might become important targets attenuating vascular endothelial growth factor (VEGF) signalling and thereby diminishing neoangiogenesis and glioblastoma growth.

Nociceptor sensitization to mechanical and thermal stimuli in pig skin in vivo.

Primary hyperalgesia to mechanical and thermal stimuli are major clinical symptoms of inflammatory pain and can be induced experimentally by ultraviolet-B (UV-B) irradiation in humans. We set-up a pig model in order to have more options for pharmacological intervention on primary hyperalgesia. Pig skin was irradiated with a dose one- to threefold higher than the minimum erythema dose (MED) and investigated for mechanical and heat responsiveness 24 and 48 h post UV-B treatment. C-fiber activation upon mechanical and thermal stimulation was assessed indirectly by extent of the axon reflex erythema (flare) measured by laser Doppler imaging. Mechanical stimulation with von Frey filaments (100 mN) induced flare responses in UV-B treated skin at 24 and 48 h, but no effect was measured in normal untreated skin. Increased mechanical stimulation (600 mN) elicited a small flare response in normal skin in an area of 1.8 cm(2) on average that was extending about 2.5 cm(2) in the UV-B irradiated sites. Thermal stimuli provoked in normal pig skin flare areas of approximately 2 cm(2) (45 degrees C, 10 s) and 4.5 cm(2) (47 degrees C, 10 s) which increased to about 3.5 cm(2) (45 degrees C) and 5.5 cm(2) (47 degrees C) following UV-B irradiation at 24 and 48 h. No significant differences of mechanically or thermally induced hypersensitivity were seen between 24 and 48 h after irradiation. We conclude that UV-B induced mechanical and heat sensitization of primary afferent nociceptors can be assessed in pig skin, providing a new human-like model of primary hyperalgesia. Sensitization of primarily mechano-insensitive (silent) nociceptors, which are underlying the flare response in humans, most probably contributes to the observation presented here.

Rapid flare development evoked by current frequency-dependent stimulation analyzed by full-field laser perfusion imaging.

We analyzed, with a new imaging technique, the rapid axon reflex flare responses in human skin upon transcutaneous delivery of electrical stimuli at 1, 5, 10 and 50 Hz in single bursts of five pulses each. Two-dimensional perfusion images covering an area of 8 x 8 cm(2) were captured at 25 Hz and their averages saved at 0.5 Hz. The stimulation caused an axon reflex flare (maximum 3 cm(2), 20 s after stimulation) that gradually resolved within 2 min. Maximum flare responses developed at 5 Hz, whereas pain ratings increased with stimulation frequency. The highest neuropeptide release at 5 Hz correlates to the discharge characteristics of mechanoinsensitive C-fibers, whereas the maximum pain intensity at 50 Hz may be attributed to the activation of A-delta fibers.

The effect of intravenous infusion of adenosine on electrically evoked hyperalgesia in a healthy volunteer model of central sensitization.

Human pain models invoking central sensitization, one of the key mechanisms of chronic pain, may be useful for characterizing new analgesics. A new model of electrical hyperalgesia can detect the efficacy of several analgesic mechanisms. Because IV adenosine can alleviate neuropathic pain, we investigated its effect on experimental sensitization. This was a double-blinded, randomized, two-period crossover study in 20 healthy volunteers. Current pulses (0.5 ms; 1 Hz) were applied intracutaneously to achieve pain rating of approximately 5 on a 0-10 numeric rating scale. Pain, areas of pinprick hyperalgesia, and tactile allodynia were assessed during the 2.5-h stimulation period. Adenosine (50 microg. kg(-1). min(-1)) and placebo were infused IV over 60 min. Additional testing was performed 24 h after each treatment. Adenosine reduced the area of pinprick hyperalgesia during the infusion compared with placebo; there was no significant effect on tactile allodynia or pain rating. The effect on hyperalgesia developed over 15 min and was significant (P < or = 0.05) for the rest of the infusion period. There was no difference between treatments at 24 h. Thus, in accordance with reports on neuropathic pain, adenosine reduced central sensitization in the human model of electrical hyperalgesia. However, adenosine did not have the long-term effects seen in patients. The model can investigate mechanisms of drugs for the treatment of chronic pain.