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Abstract Background In the SARS-CoV-2 pandemic, general and specialist Palliative Care (PC) plays an essential role in health care, contributing to symptom control, psycho-social support, and providing support in complex decision making. Numbers of COVID-19 related deaths have recently increased demanding more palliative care input. Also, the pandemic impacts on palliative care for non-COVID-19 patients. Strategies on the care for seriously ill and dying people in pandemic times are lacking. Therefore, the program ‘Palliative care in Pandemics’ (PallPan) aims to develop and consent a national pandemic plan for the care of seriously ill and dying adults and their informal carers in pandemics including (a) guidance for generalist and specialist palliative care of patients with and without SARS-CoV-2 infections on the micro, meso and macro level, (b) collection and development of information material for an online platform, and (c) identification of variables and research questions on palliative care in pandemics for the national pandemic cohort network (NAPKON). Methods Mixed-methods project including ten work packages conducting (online) surveys and qualitative interviews to explore and describe i) experiences and burden of patients (with/without SARS-CoV-2 infection) and their relatives, ii) experiences, challenges and potential solutions of health care professionals, stakeholders and decision makers during the SARS-CoV-2 pandemic. The work package results inform the development of a consensus-based guidance. In addition, best practice examples and relevant literature will be collected and variables for data collection identified. Discussion For a future “pandemic preparedness” national and international recommendations and concepts for the care of severely ill and dying people are necessary considering both generalist and specialist palliative care in the home care and inpatient setting.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motoneuron. It is associated with a life expectancy of 2-4 years after diagnosis. Individuals experience paralysis, dysphagia, respiratory failure and loss of communicative function, rendering advance care planning (ACP) critically important. This systematic review primarily aimed to internationally compare the application of advance directives (AD) and ACP in ALS. Its secondary aim was to identify ACP preferences, identify fields for future research and to generate recommendations for improving patient care through ACP., Methods: We conducted a systematic literature review and meta-analysis. Five electronic databases (Embase, Medline, Scopus, PsycInfo and CENTRAL) were searched for qualitative and quantitative primary literature from 1999 to 2024. Cross-references were used to identify additional publications. Study selection was performed based on inclusion criteria. Number and content of AD were extracted systematically. After statistical analysis consecutive meta-analysis was performed for international differences and changes over time. Quality assessment of studies was performed using the MMAT (Mixed Methods Appraisal Tool). PROSPERO Registration (June 07, 2021) : CRD42021248040., Results: A total of 998 records was screened of which 26 were included in the synthesis. An increase in publication numbers of 88.9% was observed from 1999 to 2024. Results regarding use and content of AD were heterogeneous and international differences were detected. AD were signed in 60.4% of records (1,629 / 2,696 patients). The number of AD decreased over time when separating the review period in two decades (1st 1999-2011: 78% vs. 2nd 2012-2024: 42%). Study quality was superior in qualitative and mixed method designs compared to quantitative studies., Conclusion: Further prospective studies should include detailed analyses on preferences regarding ventilation and artificial nutrition in ALS and should encompass countries of the global south. Despite the complexity of ACP with regard to individual patient needs, ACP should be part of each individual support plan for ALS patients and should specifically comprise a discussion on the preferred place of death. The available disease-specific AD documents should be preferred., (© 2024. The Author(s).)

Introduction: Better diagnosis and treatment of neuropathic cancer pain (NcP) remains an unmet clinical need. The EAPC/IASP algorithm was specifically designed for NcP diagnosis; yet, to date, there is no information on its application and accuracy., Objectives: Our aim was to determine the accuracy of the EAPC/IASP algorithm compared with the Neuropathic Special Interest Group grading system (gold standard) and to describe patients' sensory profile with quantitative sensory testing (QST)., Methods: This is a cross-sectional observational study conducted in a palliative care and pain outpatient clinic. Patients with cancer pain intensity ≥3 (numerical rating scale 0-10) were eligible. The palliative care physician applied the EAPC/IASP algorithm as a grading system to diagnose probable or definite NcP, and an independent investigator applied the gold standard and performed the QST. Sensitivity and specificity of the EAPC/IASP algorithm were measured in comparison with the gold standard results. Kruskal-Wallis and unequal variance independent-samples t tests were used to compare the QST parameters in patients with and without NcP., Results: Ninety-eight patients were enrolled from August 2020 to March 2023. Sensitivity and specificity for the EAPC/IASP algorithm were 85% (95% CI 70.2-94.3) and 98.3% (95% CI 90.8-100), respectively. Patients with NcP in contrast to patients without NcP showed cold hypoesthesia ( P = 0.0032), warm hypoesthesia ( P = 0.0018), pressure hyperalgesia ( P = 0.02), and the presence of allodynia ( P = 0.0001)., Conclusion: The results indicate a good performance of the EAPC/IASP algorithm in diagnosing NcP and the QST discriminated well between patients with and without NcP., Competing Interests: E.Z. has received honoraria from Amgen. R.R. has received fees as a speaker or for counseling services from the following companies: Aristo Pharma, Cannamedical, Hormosan, Grünenthal, Lilly & Company, Pfizer, Tilray, and Spectrum Therapeutics. S.K. has received honoraria from Nutricia Norge AS and Pfizer Norge AS. A.C. has received honoraria from Molteni, Pfizer/Eli Lilly Italia Spa, and Mundipharma. All other authors have no conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Myopathies fall under the umbrella of rare diseases, however, muscle pain is a relevant, under-recognized symptom with limited treatment options. Carbamazepine is an oral sodium channel blocker approved for the treatment of seizures and neuropathic pain. In 54 individuals receiving carbamazepine for muscle pain, we retrospectively assessed the subjective treatment response, side effects, and reasons for carbamazepine discontinuation. The underlying diagnoses leading to muscle pain were diverse, ranging from metabolic (n = 5) and other hereditary (n = 9) to acquired (n = 2) myopathies and myotonia syndromes (n = 22). Under carbamazepine (daily dose 254 ± 138 mg), patients reported a significant reduction of pain, quantified by an 11-point numeric rating scale (−1.9 ± 1.8, p < 0.001). Compared to age- and sex-matched controls, our sensory assessment revealed a significant dysfunction of Aδ-nerve fibers in patients with chronic muscle pain. Neuropathic pain components identified by the painDETECT questionnaire or quantitative sensory testing did not seem to influence the reported treatment response. Side effects (n = 18) such as fatigue, elevated liver enzymes, and diarrhea, as well as lack of pain improvement (n = 6), led to carbamazepine discontinuation in 44.4% (24/54). Mediated by dysfunctional Aδ-nerve fibers, muscle pain is common in a variety of myopathies. Carbamazepine may reduce pain levels, but comes with therapy-limiting side effects.

Background: General practitioners (GPs) are important providers of palliative home care (PHC). To deliver adequate palliative care, cooperation with specialised PHC teams is necessary. Specialised PHC is a type of care for severely ill patients by specialised providers. Little is known about the involvement of German GPs in specialised PHC., Objectives: To analyse GPs' experience with realised and desired involvement in specialised PHC. Realised involvement means GPs took part in specialised PHC patients' care. Desired involvement is GPs' hoped-for cooperation with specialised PHC teams: GPs could state whether they want to stay involved, be informed, or provide medical services themselves after referral to specialised PHC., Methods: Mixed methods design (focus group with 6 GPs; survey of 445 GPs in North Rhine, Germany, about their experiences in PHC/specialised PHC): Qualitative data was interpreted using content analysis. The authors developed a questionnaire and performed descriptive analysis based on qualitative results., Results: GPs are mostly satisfied with specialised PHC teams' care, although they report cooperation is not always optimal. GPs describe a high satisfaction with quality of care by specialised PHC teams. However, physicians with higher PC knowledge are less satisfied with specialised PHC. Also, GPs are often less involved in specialised PHC than they wish, especially when they have a higher PC qualification., Conclusion: In general, GPs are satisfied with the quality of care provided by specialised PHC teams but GPs do not always perceive cooperation as optimal. Involvement of GPs in specialised PHC needs to be improved.

Due to demographic change, the number of patients in palliative care (PC) is increasing. General Practitioners (GPs) are important PC providers who often have known their patients for a long time. PC can be demanding for GPs. However, there are few studies on the job stress factors of GPs performing PC and the potential influence of their PC training. To get more insights, a postal survey was performed with GPs in North Rhine, Germany. The questionnaire was based on a literature search, qualitative pre-studies, and the Hospital Consultants' Job Stress & Satisfaction Questionnaire (HCJSSQ). Participants state that a high level of responsibility, conflicting demands, and bureaucracy are the most important stressors they experienced in PC. The influence of PC qualification level on their perceived job stress factors is low. Only advanced but not specialist qualification shows a correlation with renumeration-related stress. Gender and work experience are more dominant influences. In our study, female GPs and physicians with more work experience tend to be more stressed. In conclusion, organisational barriers, such as administration, should be reduced and renumeration should be increased to facilitate the daily work of GPs.

Reconstructing the evolution, diversity, and paleobiogeography of North America's Late Cretaceous dinosaur assemblages require spatiotemporally contiguous data; however, there remains a spatial and temporal disparity in dinosaur data on the continent. The rarity of vertebrate-bearing sedimentary deposits representing Turonian-Santonian ecosystems, and the relatively sparse record of dinosaurs from the eastern portion of the continent, present persistent challenges for studies of North American dinosaur evolution. Here we describe an assemblage of ornithomimosaurian materials from the Santonian Eutaw Formation of Mississippi. Morphological data coupled with osteohistological growth markers suggest the presence of two taxa of different body sizes, including one of the largest ornithomimosaurians known worldwide. The regression predicts a femoral circumference and a body mass of the Eutaw individuals similar to or greater than that of large-bodied ornithomimosaurs, Beishanlong grandis, and Gallimimus bullatus. The paleoosteohistology of MMNS VP-6332 demonstrates that the individual was at least ten years of age (similar to B. grandis [~375 kg, 13-14 years old at death]). Additional pedal elements share some intriguing features with ornithomimosaurs, yet suggest a larger-body size closer to Deinocheirus mirificus. The presence of a large-bodied ornithomimosaur in this region during this time is consistent with the relatively recent discoveries of early-diverging, large-bodied ornithomimosaurs from mid-Cretaceous strata of Laurasia (Arkansaurus fridayi and B. grandis). The smaller Eutaw taxon is represented by a tibia preserving seven growth cycles, with osteohistological indicators of decreasing growth, yet belongs to an individual approaching somatic maturity, suggesting the co-existence of medium- and large-bodied ornithomimosaur taxa during the Late Cretaceous Santonian of North America. The Eutaw ornithomimosaur materials provide key information on the diversity and distribution of North American ornithomimosaurs and Appalachian dinosaurs and fit with broader evidence of multiple cohabiting species of ornithomimosaurian dinosaurs in Late Cretaceous ecosystems of Laurasia., Competing Interests: The authors have declared that no competing interests exist.

Background: The COVID-19 pandemic confronted nursing homes with a variety of challenges to ensure the provision of palliative care for residents. PallPan-Implement aimed to adapt the recommendations of the National Strategy for the Care of Seriously Ill, Dying Adults and their Families in Times of Pandemic (PALLPAN) in such a way that nursing facilities can use and implement them., Methods: Based on 33 PALLPAN recommendations, we developed a questionnaire, conducted a pilot implementation for selected nursing homes, and asked for qualitative feedback., Results: The developed questionnaire contains 22 main questions. A three-stage pilot implementation with an introductory event, processing phase, and evaluation event took place in seven facilities. The facilities evaluated the developed questionnaire as helpful. Feedback from the facilities identified three major categories: (a) requirements for facilities should be realistic to avoid frustration, (b) the creation of a pandemic plan for palliative care only is impractical, (c) measures for the psychosocial support of staff is particularly necessary, but was perceived as difficult to implement., Conclusions: The practical implementation of recommendations requires a concept and material tailored to facilities and areas. The strategy of PallPan Implement developed in this project appears to be target-oriented, well-received, and can be recommended for further implementation.

Background: There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner's corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN., Patients and Methods: Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical detection thresholds), Grooved pegboard test, and patient-reported outcomes measures (PROMS) were conducted for comparison., Results: In controls (25 females, 20 males; 24-81 years), females exhibited greater mean MC density compared with males (49.9 ± 7.1 vs 30.9 ± 4.2 MC/3 × 3 mm; P = .03). Differences existed across age by decade (P < .0001). Meissner's corpuscle density was correlated with mechanical detection (ρ = -0.51), warm detection (ρ = -0.47), cold pain (ρ = 0.49) thresholds (P < .01); and completion time on the Grooved pegboard test in both hands (P ≤ .02). At baseline, patients had reduced MC density vs age and gender-matched controls (P = .03). Longitudinal assessment of MC density revealed significant relationships with QST and PROMS. Inter-rater reliability of MC count showed an intraclass correlation of 0.96 (P < .0001)., Conclusions: The findings support the clinical utility of RCM in CIPN as it provides meaningful markers of sensory nerve dysfunction. Novel, prospective assessment demonstrated the ability to detect subclinical deficits in patients at risk of CIPN and potential to monitor neuropathy progression., (© The Author(s) 2022. Published by Oxford University Press.)

Background: In the SARS-CoV-2 pandemic, general and specialist Palliative Care (PC) plays an essential role in health care, contributing to symptom control, psycho-social support, and providing support in complex decision making. Numbers of COVID-19 related deaths have recently increased demanding more palliative care input. Also, the pandemic impacts on palliative care for non-COVID-19 patients. Strategies on the care for seriously ill and dying people in pandemic times are lacking. Therefore, the program 'Palliative care in Pandemics' (PallPan) aims to develop and consent a national pandemic plan for the care of seriously ill and dying adults and their informal carers in pandemics including (a) guidance for generalist and specialist palliative care of patients with and without SARS-CoV-2 infections on the micro, meso and macro level, (b) collection and development of information material for an online platform, and (c) identification of variables and research questions on palliative care in pandemics for the national pandemic cohort network (NAPKON)., Methods: Mixed-methods project including ten work packages conducting (online) surveys and qualitative interviews to explore and describe i) experiences and burden of patients (with/without SARS-CoV-2 infection) and their relatives, ii) experiences, challenges and potential solutions of health care professionals, stakeholders and decision makers during the SARS-CoV-2 pandemic. The work package results inform the development of a consensus-based guidance. In addition, best practice examples and relevant literature will be collected and variables for data collection identified., Discussion: For a future "pandemic preparedness" national and international recommendations and concepts for the care of severely ill and dying people are necessary considering both generalist and specialist palliative care in the home care and inpatient setting., (© 2022. The Author(s).)

Mutations in the voltage-gated sodium channel Nav1.7 are linked to human pain. The Nav1.7/N1245S variant was described before in several patients suffering from primary erythromelalgia and/or olfactory hypersensitivity. We have identified this variant in a pain patient and a patient suffering from severe and life-threatening orthostatic hypotension. In addition, we report a female patient suffering from muscle pain and carrying the Nav1.7/E1139K variant. We tested both Nav1.7 variants by whole-cell voltage-clamp recordings in HEK293 cells, revealing a slightly enhanced current density for the N1245S variant when co-expressed with the β1 subunit. This effect was counteracted by an enhanced slow inactivation. Both variants showed similar voltage dependence of activation and steady-state fast inactivation, as well as kinetics of fast inactivation, deactivation, and use-dependency compared to WT Nav1.7. Finally, homology modeling revealed that the N1245S substitution results in different intramolecular interaction partners. Taken together, these experiments do not point to a clear pathogenic effect of either the N1245S or E1139K variant and suggest they may not be solely responsible for the patients' pain symptoms. As discussed previously for other variants, investigations in heterologous expression systems may not sufficiently mimic the pathophysiological situation in pain patients, and single nucleotide variants in other genes or modulatory proteins are necessary for these specific variants to show their effect. Our findings stress that biophysical investigations of ion channel mutations need to be evaluated with care and should preferably be supplemented with studies investigating the mutations in their context, ideally in human sensory neurons.

Background: Retrospective investigation of the somatosensory profile and prediction of histologic small fiber neuropathy (SFN) in postural orthostatic tachycardia syndrome (POTS) was performed using quantitative sensory testing (QST) as a standardized noninvasive test., Methods: In this investigation, full data sets from 30 patients (age: 34.03 ± 10.82 years, n = 6 males), including results of autonomic function testing, norepinephrine values, skin biopsy, and QST, were retrospectively analyzed. The QST data were compared with healthy controls (HCs) (age: 34.20 ± 10.5 years, n = 6 males, t test: 0.95)., Results: The evaluation of all QST parameters in POTS compared with HCs yielded differences in all thermal parameters (cold detection threshold: p < 0.05, warm detection threshold: p < 0.001, thermal sensory limen: p < 0.001, cold pain threshold: p < 0.05, and heat pain threshold: p < 0.001) and in paradoxical heat sensations ( p < 0.05). Differences in nonpainful stimuli (mechanical detection threshold: p < 0.05 and vibration detection threshold: p < 0.001) were also detected. All patients who had clinical signs of SFN in combination with impairment of small fibers in QST also had SFN on skin biopsy., Conclusion: These results suggest that a non-region-specific SFN in POTS compared with controls can be detected by noninvasive QST that predicts histologic small fiber pathology., (© 2019 American Academy of Neurology.)

Background: IT systems in the healthcare field can have a marked sociotechnical impact: they modify communication habits, alter clinical processes and may have serious ethical implications. The introduction of such systems involves very different groups of stakeholders because of the inherent multi-professionalism in medicine and the role of patients and their relatives that are often underrepresented. Each group contributes distinct perspectives and particular needs, which create specific requirements for IT systems and may strongly influence their acceptance and success. In the past, needs analysis, challenges and requirements for medical IT systems have often been addressed using consensus techniques such as the Delphi technique. Facing the heterogeneous spectrum of stakeholders there is a need to develop these techniques further to control the (strong) influence of the composition of the expert panel on the outcome and to deal systematically with potentially incompatible needs of stakeholder groups. This approach uses the strong advantages a Delphi study has, identifies the disadvantages of traditional Delphi techniques and aims to introduce and evaluate a modified approach called 360-Degree Delphi. Key aspects of 360-Degree Delphi are tested by applying the approach to the needs and requirements analysis of a system for managing patients' advance directives and living wills., Methods: 360-Degree Delphi (short 360°D), as a modified Delphi process, is specified as a structured workflow with the optional use of stakeholder groups. The approach redefines the composition of the expert panel by setting up groups of different stakeholders. Consensus is created within individual stakeholder groups, but is also communicated between groups, while the iterative structure of the Delphi process remains unchanged. We hypothesize that (1) 360-Degree Delphi yields complementary statements from different stakeholders, which would be lost in classical Delphi; while (2) the variation of statements within individual stakeholder groups is lower than within the total collective. A user study is performed that addresses five stakeholder groups (patients, relatives, medical doctors, nurses and software developers) on the topic of living will communication in an emergency context. Qualitative open questions are used in a Delphi round 0. Answer texts are coded by independent raters who carry out systematic bottom-up qualitative text analysis. Inter-rater reliability is calculated and the resulting codes are used to test the hypotheses. Qualitative results are transferred into quantitative questions and then surveyed in round 1. The study took place in Germany., Results: About 25% of the invited experts (stakeholders) agreed to take part in the Delphi round 0 (three patients, two relatives, three medical doctors, two qualified nurses and three developers), forming a structured panel of the five stakeholder groups. Two raters created a bottom-up coding, and 238 thematic codes were identified by the qualitative text analysis. The inter-rater reliability showed that 44.95% of the codes were semantically similar and coded for the same parts of the raw textual replies. Based on a consented coding list, a quantitative online-questionnaire was developed and send to different stakeholder groups. With respect to the hypotheses, Delphi round 0 had the following results: (1) doctors had a completely different focus from all the other stakeholder groups on possible channels of communications with the patient; (2) the dispersion of codes within individual stakeholder groups and within the total collective - visualized by box plots - was approximately 28% higher in the total collective than in the sub-collectives, but without a marked effect size. With respect to the hypotheses, Delphi round 1 had the following results: different stakeholder groups had highly diverging opinions with respect to central questions on IT-development. For example, when asked to rate the importance of access control against high availability of data (likert scale, 1 meaning restrictive data access, 6 easy access to all data), patients (mean 4.862, Stdev +/- 1.866) and caregivers (mean 5.667, Stdev: +/- 0.816) highly favored data availability, while relatives would restrict data access (mean 2.778, stdev +/- 1.093). In comparison, the total group would not be representative of either of these individual stakeholder needs (mean 4.344, stdev +/- 1.870)., Conclusion: 360-Degree Delphi is feasible and allows different stakeholder groups within an expert panel to reach agreement individually. Thus, it generates a more detailed consensus which pays more tribute to individual stakeholders needs. This has the potential to improve the time to consensus as well as to produce a more representative and precise needs and requirements analysis. However, the method may create new challenges for the IT development process, which will have to deal with complementary or even contradictory statements from different stakeholder groups.

​INTRODUCTION: Randomised controlled trials (RCTs) have shown a positive effect of early integration of palliative care (EIPC) in various advanced cancer entities regarding patients' quality of life (QoL), survival, mood, caregiver burden and reduction of aggressiveness of treatment near the end of life. However, RCTs investigating the positive effect of EIPC for patients suffering from glioblastoma multiforme (GBM) are lacking. After modelling work identifying the specific needs of GBM patients and their caregivers, the aim of this study is to investigate the impact of EIPC in this particular patient group. ​METHODS AND ANALYSIS: The recruitment period of this multicenter RCT started in May 2019. GBM patients (n=214) and their caregivers will be randomly assigned to either the intervention group (receiving proactive EIPC on a monthly basis) or the control group (receiving treatment according to international standards and additional, regular assessment of QoL ('optimised' standard care)).The primary outcome is QoL assessed by subscales of the Functional Assessment of Cancer Therapy for brain tumour (FACT-Br) from baseline to 6 months of treatment. Secondary outcomes are changes in QoL after 12 (end of intervention), 18 and 24 months (end of follow-up), the full FACT-Br scale, patients' palliative care needs, depression/anxiety, cognitive impairment, caregiver burden, healthcare use, cost-effectiveness and overall survival. ​ETHICS AND DISSEMINATION: The study will be conducted in accordance with the Declaration of Helsinki and has been approved by the local ethics committees of the University Clinics of Cologne, Aachen, Bonn, Freiburg and Munich (LMU). Results of the trial will be submitted for publication in a peer-reviewed, open access journal and disseminated through presentations at conferences. TRIAL REGISTRATION NUMBER: German Register for Clinical Studies (DRKS) (DRKS00016066); Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Most patients with multiple myeloma (MM) suffer from chronic pain at every stage of the natural disease process. This review focuses on the most common causes of chronic pain in MM patients: (1) pain from myeloma bone disease (MBD); (2) chemotherapy-induced peripheral neuropathy as a possible consequence of proteasome inhibitor therapy (i.e., bortezomib-induced); (3) post-herpetic neuralgia as a possible complication of varicella zoster virus reactivation because of post-transplantation immunodepression; and (4) pain in cancer survivors, with increasing numbers due to the success of antiblastic treatments, which have significantly improved overall survival and quality of life. In this review, non-pain specialists will find an overview including a detailed description of physiopathological mechanisms underlying central sensitization and pain chronification in bone pain, the rationale for the correct use of analgesics and invasive techniques in different pain syndromes, and the most recent recommendations published on these topics. The ultimate target of this review was to underlie that different types of pain can be observed in MM patients, and highlight that only after an accurate pain assessment, clinical examination, and pain classification, can pain be safely and effectively addressed by selecting the right analgesic option for the right patient.

Background and Purpose: Oxycodone is a potent semi-synthetic opioid that is commonly used for the treatment of severe acute and chronic pain. However, treatment with oxycodone can lead to cardiac electrical changes, such as long QT syndrome, potentially inducing sudden cardiac arrest. Here, we investigate whether the cardiac side effects of oxycodone can be explained by modulation of the cardiac Na v 1.5 sodium channel., Experimental Approach: Heterologously expressed human Na v 1.5, Na v 1.7 (HEK293 cells) or Na v 1.8 channels (mouse N1E-115 cells) were used for whole-cell patch-clamp electrophysiology. A variety of voltage-clamp protocols were used to test the effect of oxycodone on different channel gating modalities. Human stem cell-derived cardiomyocytes were used to measure the effect of oxycodone on cardiomyocyte beating., Key Results: Oxycodone inhibited Na v 1.5 channels, concentration and use-dependently, with an IC 50 of 483 μM. In addition, oxycodone slows recovery of Na v 1.5 channels from fast inactivation and increases slow inactivation. At high concentrations, these effects lead to a reduced beat rate in cardiomyocytes and to arrhythmia. In contrast, no such effects could be observed on Na v 1.7 or Na v 1.8 channels., Conclusions and Implications: Oxycodone leads to an accumulation of Na v 1.5 channels in inactivated states, with a slow time course. Although the concentrations needed to elicit cardiac arrhythmias in vitro are relatively high, some patients under long-term treatment with oxycodone as well as drug abusers and addicts might suffer from severe cardiac side effects induced by the slowly developing effects of oxycodone on Na v 1.5 channels., (© 2018 The British Pharmacological Society.)

Background: The aim of the study was to analyse intraoral neurophysiological changes in patients with unilateral lingual nerve lesions as well as patients with Burning Mouth Syndrome (BMS) by applying a standardized Quantitative Sensory Testing (QST) protocol., Methods: The study included patients suffering from a peripheral lesion of the lingual nerve (n = 4), from BMS (n = 5) and healthy controls (n = 8). Neurophysiological tests were performed in the innervation areas of the tongue bilaterally. For BMS patients the dorsal foot area was used as reference., Results: For patients with peripheral lesion of the lingual nerve the affected side of the tongue showed increased thresholds for thermal (p < 0.05-0.001) and mechanical (p < 0.01-0.001) QST parameters, indicating a hypoesthesia and thermal hypofunction. In BMS patients, a pinprick hypoalgesia (p < 0.001), a cold hyperalgesia (p < 0.01) and cold/warmth hypoesthesia (p < 0.01) could be detected., Conclusions: The results of this study verified the lingual nerve lesion in our patients as a peripheral dysfunction. The profile showed a loss of sensory function for small and large fibre mediated stimuli. A more differentiated classification of the lingual nerve injury was possible with QST, regarding profile, type and severity of the neurologic lesion. BMS could be seen as neuropathy with variable central and peripheral contributions among individuals resulting in chronic pain.

Long term depression (LTD) is a neuronal learning mechanism after low frequency stimulation (LFS). This study compares two types of electrodes (concentric vs. matrix) and stimulation frequencies (4 and 30 Hz) to examine homo- and heterosynaptic effects indirectly depicted from the somatosensory profile of healthy subjects. Both electrodes were compared in a prospective, randomized, controlled cross-over study using 4 Hz as the conditioning LFS compared to 30 Hz (intended sham condition). Quantitative sensory testing (QST) was used to examine 13 thermal and mechanical detection and pain thresholds. Sixteen healthy volunteers (10 women, age 31.0 ± 12.7 years) were examined. Depending on the electrodes and frequencies used a divergent pattern of sensory minus signs occurred. Using LFS the concentric electrode increased thermal thresholds, while the matrix electrode rather increased mechanical including deep pain thresholds. Findings after cutaneous neuromodulation using LFS and a matrix electrode are consistent with the concept of heterosynaptic LTD in the human nociceptive system, where deep pain sensitivity was reduced after superficial stimulation of intraepidermal nerve fibres. Cutaneous neuromodulation using LFS and a matrix electrode may be a useful tool to influence deep pain sensitivity in a variety of chronic pain syndromes.

Objectives. The objective was to investigate whether a treatment with a needle stimulation pad (NSP) changes perceived pain and/or sensory thresholds in patients with chronic neck (NP) and lower back pain (BP). Methods. 40 patients with chronic NP and 42 patients with chronic BP were equally randomized to either treatment or waiting list control group. The treatment group self-administered a NSP over a period of 14 days. Pain ratings were recorded on numerical rating scales (NRSs). Mechanical detection thresholds (MDTs) and pressure pain thresholds (PPTs) were determined at the site of maximal pain and in the adjacent region, vibration detection thresholds (VDT) were measured at close spinal processes. The Northwick Park Neck Pain Questionnaire (NPQ) and the Oswestry Disability Index (ODI) were utilized for the NP and BP study, respectively. Results. NRS ratings were significantly reduced for the treatment groups compared to the control groups (NP: P = .021 and BP: P < .001), accompanied by a significant increase of PPT at pain maximum (NP: P = .032 and BP: P = .013). There was no effect on VDT and MDT. The NPQ showed also a significant improvement, but not the ODI. Conclusions. The mechanical NSP seems to be an effective treatment method for chronic NP and BP.

Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p = 0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p = 0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p = 0.006, p = 0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p = 0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients.

This study aimed to assess thermal and mechanical perception and pain thresholds in primary idiopathic restless legs syndrome and secondary restless legs syndrome associated with small fibre neuropathy. Twenty-one patients (age: 53.4 + or - 8.4, n = 3, male) with primary restless legs syndrome and 13 patients (age: 63.0 + or - 8.2, n = 1, male) with secondary restless legs syndrome associated with small fibre neuropathy were compared with 20 healthy subjects (age: 58.0 + or - 7.0; n = 2, male). Differential diagnosis of secondary restless legs syndrome associated with small fibre neuropathy was based on clinical symptoms and confirmed with skin biopsies in all patients. A comprehensive quantitative sensory testing protocol encompassing thermal and mechanical detection and pain thresholds, as devised by the German Research Network on Neuropathic Pain, was performed on the clinically more affected foot between 2 pm and 1 am when restless legs syndrome symptoms were present in all patients. Patients with primary restless legs syndrome showed hyperalgesia to blunt pressure (P < 0.001), pinprick (P < 0.001) and vibratory hyperaesthesia (P < 0.001). Patients with secondary restless legs syndrome associated with small fibre neuropathy showed thermal hypoaesthesia to cold (Adelta-fibre mediated) and warm (C-fibre mediated) (all P < 0.001) and hyperalgesia to pinprick (P < 0.001). Static mechanical hyperalgesia in primary and secondary restless legs syndrome is consistent with the concept of central disinhibition of nociceptive pathways, which might be induced by conditioning afferent input from damaged small fibre neurons in secondary restless legs syndrome.

Cytokines, particularly tumor necrosis factor-alpha, may play an important role in the mediation of mechanical hyperalgesia and autonomic signs in complex regional pain syndrome 1. We performed an IV regional block with low-dose administration of the tumor necrosis factor-alpha antibody, infliximab, in a patient with typical clinical signs of complex regional pain syndrome 1 (moderate pain, edema, hyperhidrosis, elevated skin temperature compared with the contralateral side). A significant improvement of clinical variables was observed 24 h after infliximab treatment. Almost complete remission was reached within 8 wk, but sensory signs improved only after 6 mo. No adverse events were observed.

Unlabelled: Intradermal capsaicin injection (CAP) and electrical current stimulation (ES) are analyzed in respect to patterns and test-retest reliability of pain as well as sensory and neurosecretory changes. In 10 healthy subjects, 2x CAP (50 microg) and 2x ES (5 to 30 mA) were applied to the volar forearm. The time period between 2 identical stimulations was about 4 months. Pain ratings, areas of mechanical hyperalgesia, and allodynia were assessed. The intensity of sensory changes was quantified by using quantitative sensory testing. Neurogenic flare was assessed by using laser Doppler imaging. Calcitonin gene-related peptide (CGRP) release was quantified by dermal microdialysis in combination with an enzyme immunoassay. Time course and peak pain ratings were different between CAP and ES. Test-retest correlation was high (r > or = 0.73). Both models induced primary heat hyperalgesia and primary plus secondary pin-prick hyperalgesia. Allodynia occurred in about half of the subjects. Maximum flare sizes did not differ between CAP and ES, but flare intensities were higher for ES. Test-retest correlation was higher for flare sizes than for flare intensity. A significant CGRP release could only be measured after CAP. The different time courses of pain stimulation (CAP: rapidly decaying pain versus ES: pain plateau) led to different peripheral neurosecretory effects but induced similar central plasticity and hyperalgesia., Perspective: The present study gives a detailed overview of psychophysical and neurosecretory characteristics induced by noxious stimulation with capsaicin and electrical current. We describe differences, similarities, and reproducibility of these human pain models. These data might help to interpret past and future results of human pain studies using experimental pain.

Background and Purpose: Ultrasound-accelerated thrombolysis is a promising approach toward acute stroke treatment. In previous in vitro studies, we demonstrated enhanced thrombus destruction induced by 20-kHz ultrasound. However, little is known about biological interactions of low-frequency ultrasound with brain tissue. The aim of this in vivo MRI study was to assess safety aspects of transcranial low-frequency ultrasound in rats., Methods: The cranium of 33 male Wistar rats was sonificated for 20 minutes (20-kHz continuous wave). Power output was varied between 0 and 2.6 W/cm2. Tympanal and rectal temperature was monitored. Diffusion-weighted imaging and T2-weighted imaging was performed before and 4 hours, 24 hours, and 5 days after sonification. Apparent diffusion coefficients (ADCs) and T2 relaxation time (T2-RT) were measured in regions of interest in the cortex and the basal ganglia. The animals were euthanized for histological evaluation thereafter., Results: Tympanal temperature increased significantly during insonation with 1.1 and 2.6 W/cm2. ADCs decreased significantly at 0.5 and 1.1 W/cm2, indicating cytotoxic edema. T2-RT increased significantly in the 0.5 and 1.1 W/cm2 group, consistent with vasogenic edema. No changes were detectable in the low-power output group (0.2 W/cm2). After sonification with 2.6 W/cm2, a significant loss of neurons could be detected on histopathology. Furthermore, 3 animals developed circumscript cortical lesions that could be identified as parenchymal necrosis., Conclusions: Low-frequency ultrasound caused vasogenic and cytotoxic brain edema and intracerebral necrosis in a dose-dependent fashion. This study indicates therapeutic low-frequency ultrasound as being potentially harmful and underlines the necessity of careful evaluation in further animal models.

Dysarthria is a frequent symptom in cerebral ischaemia. However, speech characteristics of these patients have not previously been investigated in relation to lesion site in a prospective study. We investigated the auditory perceptual features in 62 consecutive patients with dysarthria due to a single, non-space-occupying cerebral infarction confirmed by MRI. Standardized speech samples of all patients were stored within 72 h after stroke onset using a digital tape recorder. Speech samples were assessed independently by two experienced speech therapists, who were unaware of the clinical and neuroradiological findings, using an interval scale ranging from 0 to 6. Separately assessed were features of articulation, phonation, prosody, and the global severity for a total of 31 items. Extracerebellar infarctions (85.5%) were located in the lower motor cortex (14.5%), striatocapsular region (46.8%) and base of the pons (24.2%). Isolated cerebellar infarctions were present in 14.5% of patients. There was a strong correlation between the findings of both examiners, showing identical scores, or only minor differences (<1 on the assessment scale) for 80% of all items. The average severity of dysarthria was 2.9 +/- 1.3. Articulatory abnormalities were the predominant deviation characteristics, affecting in particular the production of consonants. However, phonatory and prosodic abnormalities were also frequently observed speech characteristics. As revealed by factor analysis of speech characteristics the total severity of dysarthria was mainly influenced by the impairment of articulation. Speech parameters describing characteristics of articulation and prosody showed significant side-to-side and area differences, while this effect was lacking for any voice parameter. Left cerebral lesions showed a more severe overall impairment of speech and articulation, independent of lesion topography. Thirty-eight of 62 patients were available for follow-up. Speech evaluation showed normal speech within weeks in 15 out of 38 patients (39.5%). In the other 23 patients overall severity of dysarthria was mild. This is the first prospective study which describes speech characteristics of dysarthria due to acute unilateral cerebral infarctions. We could demonstrate that dysarthria in extracerebellar infarctions was more frequently caused by left-sided lesions and that the severity of dysarthria was more pronounced in left-sided lesions independent from lesion topography. All extracerebellar lesions were located along the course of the cortico-bulbar tract fibres. Compatible with a common pathophysiological basis of dysarthria in these patients, none of the 31 speech items differed significantly between subcortical and brainstem lesions.

Background and Aims: It has not been clarified if botulinum toxin (BTX) injection leads to muscle spindle dysfunction in man. This study aimed to test the hypothesis that BTX application reduces the facilitation of a magnetic evoked response (MEP)., Methods: We used the vibration induced facilitation of an MEP of the sternocleidomastoid muscle (SCM) as a surrogate marker for muscle spindle function in 20 healthy subjects and 10 patients with idiopathic rotational torticollis in whom BTX was injected unilaterally., Results: The increase in the amplitude and area of the MEPs in the clinically not affected and untreated SCM of the patients did not differ significantly from the controls. At baseline, the vibration induced increase in the affected SCM of the patients was significantly lower than in the control group. Six weeks after BTX application, the observed facilitation decreased significantly (amplitude and area: p<0.001) when compared with baseline values. Twelve weeks after BTX application, facilitation showed an increase in the values of the amplitude (p<0.001), but not of the area when compared with the six week examination., Conclusions: We demonstrated that the vibration induced MEP facilitation in the SCM of patients with torticollis significantly decreased six weeks after BTX application and again increased after 12 weeks in part when looking at MEP amplitude. This observation is suggestive of denervation and reinnervation of the muscle spindles after BTX injection.

Objective: Pathophysiology explaining pain in diabetic neuropathy (DN) is still unknown., Research Design and Methods: Thirty patients with peripheral DN (17 men and 13 women; mean age 52.4 +/- 2.5 years) were investigated. Fifteen patients had neuropathic pain, and 15 patients were free of pain. Patients were followed over 2 years and examined at the beginning and thereafter every 6 months. Clinical severity and painfulness of the DN were assessed by the neuropathy impairment score and visual analog scales (VASs). Cold and warm perception thresholds as well as heat pain thresholds were obtained for evaluation of Adelta- and C-fibers. Nerve conduction velocities (NCVs) and vibratory thresholds were recorded for analysis of thickly myelinated fibers. Moreover, for assessment of cardiac vagal function, heart rate variability (HRV) was evaluated. In order to reduce day-to-day variability of pain, mean values of the five time points over 2 years were calculated and used for further analysis. Data were compared with an age- and sex-matched control group of healthy volunteers., Results: There were significant differences regarding electrophysiological studies, HRV and quantitative sensory testing (QST) between patients and healthy control subjects (P < 0.001). Generally, patients with neuropathic pain were indistinguishable from pain-free patients. In the pain group, however, VAS pain ratings were correlated to the impairment of small-fiber function (cold detection thresholds, P = 0.02; warm detection thresholds, P = 0.056)., Conclusions: Intensity of pain in painful DN seems to depend on small nerve fiber damage and deafferentation., (Copyright 2004 American Diabetes Association)