Advance directives in amyotrophic lateral sclerosis - a systematic review and meta-analysis.

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.

[N-Check: nerve check to document chemotherapy-induced peripheral neuropathy (CIPN) in incurable cancer]. / N-Check: Nervencheck zur Erfassung einer chemotherapieinduzierten peripheren Neuropathie (CIPN) bei nichtheilbarer Krebserkrankung.

Chemotherapy-induced polyneuropathy (CIPN) encompasses a spectrum of symptoms ranging from hypoesthesia with impaired gait, stance and fine motor skills to painful dysesthesia and allodynia and significantly impairs the quality of life of those affected. In the present pilot study, quantitative sensory testing (QST) was used to investigate CIPN as a common adverse effect of cytostatic drugs in patients with incurable cancer. The QST is a standardized examination procedure that is not yet routinely used in cancer patients. It is used to examine thermal and mechanical perception and pain thresholds to record the subjectively experienced pain phenotype. In the N­Check pilot project, the QST was used before and after tumor-specific, potentially CIPN-inducing treatment and the data collected was compared in a pre-post analysis. In addition, the specific effects of CIPN on the health-related quality of life of patients treated primarily with a palliative intention were recorded using the Functional Assessment for Cancer Therapy-General (FACT-G) questionnaire. Overall, the patients showed significant heat hypoalgesia after chemotherapy as a sign of damage to small nerve fibers. In addition, there were signs of deterioration of the quality of life. The feasibility of QST in patients with incurable cancer and palliative, neurotoxic chemotherapy was demonstrated in this pilot study.

[Neuropathic pain as a symptom in autonomic neuropathies and other rare diseases : Small fiber neuropathy: its recognition, diagnosis, and treatment]. / Neuropathische Schmerzen als Symptom bei autonomen Neuropathien und anderen seltenen Erkrankungen : Kleinfaserneuropathie erkennen, diagnostizieren und behandeln.

BACKGROUND: Neuropathic pain is difficult to diagnose and treat. Small fiber neuropathy (SFN) flies under the radar of nerve conduction studies. OBJECTIVES: The importance of a structured patient history and physical examination in the context of neuropathic pain is emphasized. Describing SFN as an important cause, the authors consider rare but partially treatable differential diagnoses. They conclude that autonomic symptoms are frequently associated, often presenting with diverse symptoms. METHODS: A selective literature research to present SFN symptoms as well as differential diagnostic and therapeutic steps in the context of SFN and rare diseases focusing on the autonomic nervous system. RESULTS: Neuropathic pain significantly reduces quality of life. To shorten the time until diagnosis and to initiate therapy, the authors recommend a structured patient history including sensory plus and minus symptoms and non-specific autonomic signs. If the initial search for the cause is not successful, rare causes such as treatable transthyretin (ATTR) amyloidosis and Fabry's disease or autoimmune causes should be considered, particularly in the case of progressive and/or autonomic symptoms. CONCLUSION: The diagnosis and therapy of rare SFN requires interdisciplinary collaboration and, in many cases, a referral to specialized centers to achieve the best patient care.

Skin biopsy reveals generalized small fibre neuropathy in hypermobile Ehlers-Danlos syndromes.

BACKGROUND AND PURPOSE: Ehlers-Danlos syndromes are hereditary disorders of connective tissue that are characterized by joint hypermobility, skin hyperextensibility and tissue fragility. The most common subtype is the hypermobile type. In addition to symptoms of small fibre neuropathy (SFN) due to damage to the small peripheral nerve fibres, with degeneration of the distal nerve endings, autonomic disorders such as postural tachycardia syndrome (PoTS) are frequently reported features in patients with hypermobile Ehlers-Danlos syndrome (hEDS). To date, the underlying pathophysiological mechanisms are still not completely understood. STUDY PURPOSE: To better understand pathophysiological mechanisms of small fiber neuropathy and autonomic neuropathy in hypermobile Ehlers-Danlos Syndromes. METHODS: We prospectively investigated 31 patients with hEDS compared to 31 healthy controls by using skin biopsy, quantitative sensory testing, tilt-table testing, the painDetect, Small Fibre Neuropathy Screening List and the COMPASS-31 (Composite Autonomic Symptom Score 31) questionnaire. RESULTS: Nineteen (61%) patients with hEDS were diagnosed with SFN, and 10 (32%) fulfilled the criteria for PoTS. Patients with hEDS had significantly higher heart rates than controls. According to quantitative sensory testing, these patients had generalized thermal and tactile hypesthesia. Skin biopsy revealed significantly reduced intraepithelial nerve fibre density proximally (thigh) and distally (lower leg) in patients compared to controls. This was consistent with various complaints of pain and sensory disturbances in both the proximal and distal body regions. CONCLUSION: These results confirm histologically proven SFN as a common feature in patients with hEDS, revealing a generalized distribution of nerve fibre loss. Regarding the frequently reported autonomic and neuropathic dysfunctions, the findings support SFN as an important, but not the only, underlying pathomechanism.

[Postoperative pain experience after proximal femur fracture in dementia]. / Postoperatives Schmerzerleben nach proximaler Femurfraktur bei Demenz.

BACKGROUND: The present study aimed to assess the postoperative pain experience in cognitive deficit patients with special reference to sensory or affective pain quality. METHODS: Nineteen patients with normal cognition up to cognitive impairments according to the DemTect screening-tool were studied regarding their postoperative pain experience after proximal femur fracture. The numerical rating scale (NRS), the cognitive DemTect questionnaire, the pain sensation questionnaire (SES), and a quantitative sensory test (QST) were used as examination instruments. RESULTS: The mean ± SD age of the patients was 83.8 ± 10.0 years. Of the 19 patients, 6 (31.6%) had normal cognitive abilities. In 4 patients (21.1%) there were indications of mild cognitive impairments, and in 9 patients (47.4%) the suspicions of the presence of dementia arose. The mean postoperative pain intensity (NRS) was 4.0 (1.6). With comparable analgesic therapy, the reported pain intensities did not differ between the three patient groups with different cognitive impairments and the first three postoperative treatment days. There were no statistically significant differences between the groups for the sensory or affective total scores of the pain sensation scale. The QST parameters deep pain (PPT), superficial mechanical pain after needle stimulation (MPT), and the superficial sensitivity to light touch stimuli (MDT) showed a significantly increased sensitivity of the operated side. For the sensation of vibration (VDT) no differences between operated and healthy extremities could be proven. DISCUSSION: The postoperative pain experience does not differ between patients with normal and limited cognition. The quantitative sensory testing showed mechanical hyperalgesia in the operated area. The study points to the importance of adequate postoperative pain management even in those with dementia.

The Value of In Vivo Reflectance Confocal Microscopy as an Assessment Tool in Chemotherapy-Induced Peripheral Neuropathy: A Pilot Study.

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.

[Perceptions on the use of opioids: focus on COVID-19 : Free-text analysis of a survey in anesthesiology/intensive care, internal medicine, and palliative care]. / Wahrnehmungen zum Umgang mit Opioiden: Fokus COVID-19 : Freitext-Analyse einer Umfrage in Anästhesiologie/Intensivmedizin, Innerer Medizin und Palliativmedizin.

BACKGROUND: Opioids efficiently manage pain and dyspnea. However, guidelines on symptom management with opioids differ, which may lead to uncertainty among medical staff concerning opioid indication and ethical implication, especially when caring for COVID-19 patients. AIMS: We aimed to examine the perception of morphine/opioid (M/O) administration for symptom control within and outside palliative care, including care for COVID-19 patients, among members of the German associations for palliative medicine, internal medicine, anesthesiology and intensive care. METHODS: Participants received an anonymized online questionnaire via Survey Monkey® (Momentive Inc., San Mateo, CA, USA) regarding their general perception of symptom management with M/O. These results have been published elsewhere. For systematic and structural analysis of comments in the free-text field, we chose Phillip Mayring's method of summarizing qualitative content analysis. RESULTS: Of the n = 2202 persons who participated, 339 wrote comments in the free-text field which were categorized as follows: main categories 1) personal perceptions of COVID-19 patients, 2) administration and effect of M/O, 3) observations within the palliative care field, 4) imparting knowledge concerning M/O usage and palliative care, and 5) others. CONCLUSIONS: Some participants reported very personal perceptions and deficits of the healthcare system, especially when caring for COVID-19 patients. Uniform interdisciplinary guidelines for symptom control, more education, and support by trained staff confident in symptom control should be increasingly considered in the future.

[Perceptions on the use of opioids in COVID-19 : A survey of members of the German Association for Palliative Medicine]. / Wahrnehmungen zum Umgang mit Opioiden bei COVID-19 : Eine Umfrage unter Mitgliedern der Deutschen Gesellschaft für Palliativmedizin.

BACKGROUND: Opioids efficiently alleviate pain and dyspnea. However, guidelines on symptom management with opioids differ, which may lead to an uncertainty concerning opioid indication and ethical implication among medical staff, especially when caring for COVID-19 patients. AIMS: We aimed to examine the perception of members of the German Association for Palliative Medicine (DGP) concerning the administration of morphine as the gold standard opioid (subsequently termed M/O) for symptom control within and outside of a palliative care (PC) setting, including care for COVID-19 patients. METHODS: DGP members received an anonymized online questionnaire (Survey Monkey®) containing questions regarding their perception of symptom management with M/O in general and in particular concerning COVID-19 patients. Participants were asked to rate their perception within and outside of a PC setting. RESULTS: Of the 6129 DGP members, N = 506 participated. DGP physicians and nurses perceived handling of M/O as "certain and confident" (98%) and "clearly regulated" within PC (95%) but rated it significantly lower for outside PC (48%/38%). When caring for COVID-19 patients, handling of M/O was even less often rated "certain and confident" (26%) or "clearly regulated" (23%) for outside PC. Dyspnea (99%/52%), relief from the dying process (62%/37%), restlessness (30%/15%) and fear or panic (27%/13%) were more frequently rated as general indications for morphine within versus outside PC. Most participants (89%) wished to involve palliative care consultation teams. CONCLUSIONS: DGP members perceived substantial uncertainty in the handling of M/O for medical fields outside PC. Uniform interdisciplinary guidelines for symptom control, more education, and involvement of a PC consultation team should be increasingly considered in the future.

Availability as key determinant in the palliative home care setting from the patients' and family caregivers' perspectives: A quantitative-qualitative-content analysis approach.

OBJECTIVE: A sense of security is important in palliative home care. Yet, knowledge about which components contribute most to feeling secure from the patients' and family caregivers' perspectives, especially since the introduction of specialist palliative home care, is sparse. The goal of the current study was to determine the key components contributing to a sense of security and how they relate to each other as experienced by patients and family caregivers in specialist and generalist palliative home care. METHODS: The current sub-study, as part of a larger study, was performed in different regions in Germany. Palliative care patients and family caregivers of at least 18 years of age, being cared for at home were interviewed using semi-structured interview guides following a three-factor model and analyzed by using a combined quantitative-qualitative-content approach. RESULTS: One hundred and ninty-seven patients and 10 carers completed interviews between December 2017 and April 2019. The majority of patients were diagnosed with an oncological disease. Sense of security was mentioned particularly often suggesting its high relevance. We identified nine subcategories that were all mentioned more frequently by specialist than generalist palliative home care recipients in the following order of priority and relation: (i) patient-centeredness: availability, provision of information/education, professional competence, patient empowerment, and trust (ii) organizational work: comprehensive responsibility, external collaboration, and internal cooperation, and (iii) direct communication. SIGNIFICANCE OF RESULTS: The work of specialist palliative home care services in particular was perceived as very effective and beneficial. Our findings confirm a previously developed three-factor model allowing for generalizability and revealed that availability was most important for improving the sense of security for effective palliative home care.

360-degree Delphi: addressing sociotechnical challenges of healthcare IT.

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.

Clinical Effectiveness and Potential Survival Benefit of US-Guided High-Intensity Focused Ultrasound Therapy in Patients with Advanced-Stage Pancreatic Cancer.

PURPOSE: Pancreatic cancer (PaC) is a life-limiting tumor with a wide range of incapacitating symptoms such as cancer pain in more than 80 % of patients. This prospective interventional study addresses the clinical effectiveness of ultrasound-guided high-intensity focused ultrasound (HIFU) treatment for patients with advanced-stage PaC, including pain perception, tumor size and survival benefit. MATERIALS AND METHODS: 50 patients with late-stage PaC underwent HIFU. Clinical assessment included evaluation of tumor volume by imaging and pain burden (pain severity, pain sensation, interference with daily activities) using the Brief Pain Inventory at baseline and follow-up. Median overall survival, progression-free survival and time to local progression were estimated using Kaplan-Meier analysis. RESULTS: In 84 % of patients, significant early relief of cancer-induced abdominal pain was achieved by HIFU independent of metastatic status; it persisted during follow-up. Tumor volume reduction was 37.8 ±â€Š18.1 % after 6 weeks and 57.9 ± 25.9 % after 6 months. 21 % of HIFU-treated patients had local tumor progression with a median time of 14.4 months from intervention. The median overall survival and progression-free survival were 16.2 and 16.9 months from diagnosis and 8.3 and 6.8 months from intervention. CONCLUSION: In patients with advanced pancreatic cancer and otherwise limited treatment options, HIFU resulted in significant early and long-lasting pain relief and tumor size reduction over time independent of metastatic status. Clinical data suggest an additional potential survival benefit.

Accuracy of the Distress Thermometer for home care patients with palliative care needs in Germany.

OBJECTIVE: Our aim was to examine the accuracy of the German version of the Distress Thermometer (DT) compared with the Hospital Anxiety and Depression Scale (HADS) in patients with palliative care needs living at home. METHOD: Ours was a 15-month cross-sectional study beginning in September of 2013 in Germany with consecutive patients cared for by a palliative home care service. The survey was implemented during the initial visit by a home care team. Patients were excluded if they were under 18 years of age, mentally or physically unable to complete the assessment questionnaires as judged by their healthcare worker, or unable to understand the German language. During the first encounter, the DT and HADS were applied, and sociodemographic and medical data were collected. RESULTS: A total of 89 persons completed both the HADS and DT questionnaires (response rate = 59.7%; mean age = 67 years; female = 55.1%; married = 65.2%; living home with relatives = 73.0%; oncological condition = 92.1%; Karnofsky Performance Scale [KPS] score: 0-40 = 30.3%, 50-70 = 57.3%, >80 = 6.7%). The mean DT score was 6.3 (±2.3), with 84.3% of participants scoring above the DT cutoff (≥4). The mean HADStotal score was 17.9 (±7.8), where 64% of participants had a total HADS score (HADStotal) ≥15, 51.7% reported anxiety (HADSanxiety ≥ 8), and 73% reported depression (HADSdepression ≥ 8). Using the HADS as a gold standard, a DT cutoff score ≥5 was optimal for identifying severe distress in patients with palliative care needs, with a sensitivity of 93.0%, a specificity of 34.4%, a positive predictive value (PPV) of 73.3%, and likelihood ratios LR+ = 1.42 (<3) and -LR = 0.203 (<0.3). SIGNIFICANCE OF RESULTS: The DT performed satisfactorily compared to the HADS in screening for distress in our study and can be employed as an instrument for identification of patients with distress. Consequent to the high prevalence of distress, we recommend its routine use for screening distressed persons at home with palliative care needs in order to offer adequate support.

Profiling intraoral neuropathic disturbances following lingual nerve injury and in burning mouth syndrome.

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.

Tapentadol Prolonged Release for Chronic Pain: A Review of Clinical Trials and 5 Years of Routine Clinical Practice Data.

Tapentadol prolonged release (PR) for the treatment of moderate to severe chronic pain combines 2 modes of action. These are µ-opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule that allow higher analgesic potency through modulation of different pharmacological targets within the pain transmitting systems. At the same time, this can also serve as a clue for modulation of different pain-generating mechanisms according to nociceptive, neuropathic, or mixed pain conditions. Tapentadol PR has now been on the market for 5 years, with over 4.6 million people treated worldwide. A panel of pain specialists convened in Germany to review the clinical program and to discuss the role of tapentadol PR in the management of chronic pain. The clinical study program demonstrated effective and generally well-tolerated treatment for up to 2 years in a broad range of chronic pain conditions, including those with neuropathic pain components. This was confirmed in routine clinical practice observations. Head-to-head studies with World Health Organization (WHO) III opioids such as oxycodone controlled release and oxycodone/naloxone PR showed at least comparable pain relief in the treatment of moderate-to-severe musculoskeletal pain. Rotation from poorly tolerated WHO III opioids to tapentadol PR provided effective pain relief and better symptom control for musculoskeletal pain compared to previous medication. Functionality, health status and quality of life also improved under tapentadol PR treatment. The gastrointestinal tolerability profile was more favorable compared to other tested WHO III opioids. Tapentadol PR has a good safety profile and no evidence of acquired tolerance from the long-term data so far collected. Overall, tapentadol PR represents an effective and generally well-tolerated alternative to "classical" opioidergic drugs.

High-intensity focused ultrasound (HIFU) for pancreatic carcinoma: evaluation of feasibility, reduction of tumour volume and pain intensity.

OBJECTIVES: Prognosis of patients with locally advanced pancreatic adenocarcinoma is extremely poor. They often suffer from cancer-related pain reducing their quality of life. This prospective observational study aimed to evaluate feasibility, local tumour response, and changes in quality of life and symptoms in Caucasian patients with locally advanced pancreatic cancer treated by ultrasound-guided high-intensity focused ultrasound (HIFU). METHODS: Thirteen patients underwent HIFU, five with stage III, eight with stage IV UICC disease. Ten patients received simultaneous palliative chemotherapy. Postinterventional clinical assessment included evaluation of quality of life and symptom changes using standardized questionnaires. CT and MRI follow-up evaluated the local tumour response. RESULTS: HIFU was successfully performed in all patients. Average tumour reduction was 34.2 % at 6 weeks and 63.9 % at 3 months. Complete or partial relief of cancer-related pain was achieved in 10 patients (77 %), five of whom required less analgesics for pain control. Quality of life was improved revealing increased global health status and alleviated symptoms. HIFU treatment was well tolerated. Eight patients experienced transient abdominal pain directly after HIFU. CONCLUSIONS: HIFU ablation of pancreatic carcinoma is a feasible, safe and effective treatment with a crucial benefit in terms of reduction of tumour volume and pain intensity. KEY POINTS: • US-guided HIFU is feasible and safe for patients with unresectable pancreatic cancer. • HIFU can considerably reduce tumour volume and cancer-related pain. • Patients treated with HIFU experienced significant and lasting reduction of pain intensity. • HIFU has a crucial clinical benefit for patients with pancreatic cancer.

Reduced Gray Matter Volume and Cortical Thickness in Patients With Small-Fiber Neuropathy.

Small-fiber neuropathy (SFN) is defined by degeneration or dysfunction of peripheral sensory nerve endings. Central correlates have been identified on the level of gray matter volume (GMV) and cortical thickness (CT) changes. However, across SFN etiologies knowledge about a common structural brain signature is still lacking. Therefore, we recruited 26 SFN patients and 25 age- and sex-matched healthy controls to conduct voxel-based- and surface-based morphometry. Across all patients, we found reduced GMV in widespread frontal regions, left caudate, insula and superior parietal lobule. Surface-based morphometry analysis revealed reduced CT in the right precentral gyrus of SFN patients. In a region-based approach, patients had reduced GMV in the left caudate. Since pathogenic gain-of-function variants in voltage-gated sodium channels (Nav) have been associated with SFN pathophysiology, we explored brain morphological patterns in a homogenous subsample of patients carrying rare heterozygous missense variants. Whole brain- and region-based approaches revealed GMV reductions in the bilateral caudate for Nav variant carriers. Further research is needed to analyze the specific role of Nav variants for structural brain alterations. Together, we conclude that SFN patients have specific GMV and CT alterations, potentially forming potential new central biomarkers for this condition. Our results might help to better understand underlying or compensatory mechanisms of chronic pain perception in the future. PERSPECTIVE: This study reveals structural brain changes in small-fiber neuropathy (SFN) patients, particularly in frontal regions, caudate, insula, and parietal lobule. Notably, individuals with SFN and specific Nav variants exhibit bilateral caudate abnormalities. These findings may serve as potential central biomarkers for SFN and provide insights into chronic pain perception mechanisms.

Application and accuracy of the EAPC/IASP diagnostic algorithm for neuropathic cancer pain and quantitative sensory testing profile in patients with pain due to cancer.

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.

Interindividual variability in cold-pressor pain sensitivity is not explained by peripheral vascular responding and generalizes to a C-nociceptor-specific pain phenotype.

ABSTRACT: Pain sensitivity of healthy subjects in the cold-pressor (CP) test was proposed to be dichotomously distributed and to represent a pain sensitivity trait. Still, it has not been systematically explored which factors influence this pain sensitivity readout. The aim of this study was to distinguish potential contributions of local tissue-related factors such as perfusion and thermoregulation or gain settings in nociceptive systems. Cold-pressor-sensitive and CP-insensitive students screened from a medical student laboratory course were recruited for a CP retest with additional cardiovascular and bilateral local vascular monitoring. In addition, comprehensive quantitative sensory testing according to Deutscher Forschungsverbund Neuropathischer Schmerz standards and a sustained pinch test were performed. Cold pressor was reproducible across sessions (Cohen kappa 0.61 ± 0.14, P < 0.005). At 30 seconds in ice water, CP-sensitive subjects exhibited not only more pain (78.6 ± 26.3 vs 29.5 ± 17.5, P < 0.0001) but also significantly stronger increases in mean arterial blood pressure (12.6 ± 9.3 vs 5.6 ± 8.1 mm Hg, P < 0.05) and heart rate (15.0 ± 8.2 vs 7.1 ± 6.2 bpm, P < 0.005), and lower baroreflex sensitivity, but not local or vasoconstrictor reflex-mediated microcirculatory responses. Cold-pressor-sensitive subjects exhibited significantly lower pain thresholds also for cold, heat, and blunt pressure, and enhanced pain summation, but no significant differences in Aδ-nociceptor-mediated punctate mechanical pain. In conclusion, differences in nociceptive signal processing drove systemic cardiovascular responses. Baroreceptor activation suppressed pain and cardiovascular responses more efficiently in CP-insensitive subjects. Cold-pressor sensitivity generalized to a pain trait of C-fiber-mediated nociceptive channels, which was independent of local thermal and vascular changes in the ice-water-exposed hand. Thus, the C-fiber pain trait reflects gain setting of the nociceptive system.

Painful stimulation increases functional connectivity between supplementary motor area and thalamus in patients with small fibre neuropathy.

BACKGROUND: The lead symptom of small fibre neuropathy (SFN) is neuropathic pain. Recent functional magnetic resonance imaging (fMRI) studies have indicated central changes in SFN patients of different etiologies. However, less is known about brain functional connectivity during acute pain processing in idiopathic SFN. METHODS: We conducted fMRI with thermal heat pain application (left volar forearm) in 32 idiopathic SFN patients and 31 healthy controls. We performed functional connectivity analyses with right supplementary motor area (SMA), left insula, and left caudate nucleus (CN) as seed regions, respectively. Since pathogenic gain-of-function variants in voltage gated sodium channels (Nav) have been linked to SFN pathophysiology, explorative connectivity analyses were performed in a homogenous subsample of patients carrying rare heterozygous missense variants. RESULTS: For right SMA, we found significantly higher connectivity with the right thalamus in SFN patients compared to controls. This connectivity correlated significantly with intraepidermal nerve fibre density, suggesting a link between peripheral and central pain processing. We found significantly reduced connections between right SMA and right middle frontal gyrus in patients with Nav variants. Likewise, connectivity between left CN and right frontal pole was decreased. CONCLUSIONS: Aberrant functional connectivity in SFN is in line with previous research on other chronic pain syndromes. Functional connectivity changes may be linked to SFN, highlighting the need to determine if they result from peripheral changes causing abnormal somatosensory processing. This understanding may be crucial for assessing their impact on painful symptoms and therapy response. SIGNIFICANCE STATEMENT: We found increased functional connectivity between SMA and thalamus during painful stimulation in patients with idiopathic SFN. Connectivity correlated significantly with intraepidermal nerve fibre density, suggesting a link between peripheral and central pain processing. Our findings emphasize the importance of investigating functional connectivity changes as a potential feature of SFN.