Electrical matrix stimulation suppresses acute itch independently of activation of sleeping nociceptors.

INTRODUCTION: Itch can be reduced by pain. Activation of sleeping nociceptors (CMi) is a crucial mechanism for the peripheral component of intense and long-lasting pain. Thus, activation of CMi might be especially effective in itch reduction. Electrical stimulation using sinusoidal pulses activates CMi with tolerable pain intensity, whereas short rectangular pulses with low intensity do not. In humans, histaminergic itch is mediated by histamine-sensitive CMi, whereas other pruritogens activate polymodal nociceptors (CM). METHODS: In a psychophysical approach in a balanced crossover repeated-measures design in healthy volunteers, we activated nociceptors by two different electrical stimulation paradigms via a matrix electrode: 4 Hz sinusoidal pulses that activate C-nociceptors including CMi or 4 Hz rectangular stimuli to activate nociceptors excluding CMi. After 5-min stimulation, itch was induced by either histamine iontophoresis or application of cowhage spicules. Itch ratings were assessed via a numerical rating scale (NRS). RESULTS: Electrical 4 Hz sine wave stimulation (0.1 mA) with low pain ratings of 1.5 (NRS; 0-10) induced an axon reflex erythema (3 cm2 ), indicating activation of CMi, whereas rectangular 0.2 ms pulses (average 0.91 mA) with the same pain rating did not. Both electrical stimulation paradigms reduced itch magnitude over time evoked by either histamine or cowhage to a similar extent. Peak maximum itch evoked by histamine was reduced by both stimulation paradigms, but not cowhage maximum itch. DISCUSSION: Since electrical stimulation with the rectangular pulse paradigm reduces itch to a similar extent as the sine wave stimulation paradigm, the input of CMi is not necessarily required for itch suppression. The input of A-fibres and polymodal nociceptors, similarly, as also achieved by scratching, seems to be sufficient for both forms of chemically evoked itch. SIGNIFICANCE: Since activation of CMi does not provide additional benefit for itch suppression, spinal pain pathways transmitted via CM versus CMi have differential effects on itch-processing circuits. This is important knowledge for using electrical matrix stimulation as itch suppressor since activation of sleeping nociceptors either requires significantly painful stimulation paradigms or specialized stimulation paradigms as sinusoidal pulses. An alternative approach using half-sine wave pulses with low pain intensity activating specifically polymodal nociceptors to suppress itch via matrix electrode stimulation may be considered.

National strategy for palliative care of severely ill and dying people and their relatives in pandemics (PallPan) in Germany - study protocol of a mixed-methods project.

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.

Quantitative sensory testing (QST). English version.

Quantitative sensory testing (QST) is a standardized and formalized clinical sensitivity test. Testing describes a subjective (psychophysical) method that entails a cooperation of the person to be examined. Within its framework, calibrated stimuli are applied to capture perception and pain thresholds, thus providing information on the presence of sensory plus or minus signs. The presented QST battery imitates natural thermal or mechanical stimuli. The aim is to acquire symptom patterns of sensory loss (for the functioning of the thick and thin nerve fibers) as well as a gain of function (hyperalgesia, allodynia, hyperpathia) with a simultaneous detection of cutaneous and deep tissue sensibility. Most of the tested QST parameters are normally distributed only after a logarithmic transformation (secondary normal distribution)-except the number of paradoxical heat sensations, of cold and heat pain thresholds, and vibration detection thresholds. A complete QST profile can be measured within 1 h. QST is suitable not only for clinical trials but also in practice as a diagnostic method to characterize the function of the somatosensory system-from the peripheral nerve fiber receptor to the projection pathways to the brain.

Matrix stimulation in cancer pain: Methodology, safety and effectiveness.

BACKGROUND: This feasibility study addresses the applicability of matrix electrodes for the reduction of ongoing pain in cancer patients via low-frequency electrical stimulation (LFS). METHODS: Low-frequency matrix stimulation (4 Hz) was applied to the skin within the 'Head's zones' referring to the tumour localization of cancer pain patients. Pain at baseline was compared to a 3-day treatment interval consisting of 5 min of matrix stimulation in the morning and evening followed by a 3-day follow-up period without therapy. Main outcome parameters included numeric rating scale values (rating scale 0-100), painDETECT, HADS, and German pain questionnaire, as well as the opioid intake, calculated as the oral morphine equivalent (OME). RESULTS: Twenty patients with cancer pain (aged 64.4 ± 10.3; 9 women) were examined. In the majority of patients, the pain was classified as nociceptive. The mean pain reduction achieved by matrix therapy was 30%, under stable daily controlled-release opioid doses between 177 and 184 mg/day (OME). Seventeen patients (85%) were responders, defined by a pain reduction of at least 30%, while four responders experienced a pain reduction of over 50%. The only side effect was short-term erythema. CONCLUSION: Findings are consistent with the concept of synaptic long-term depression in cancer pain induced after conditioning LFS. Despite the short, but well-tolerated, treatment duration of 2 × 5 min/day, effects persisted throughout the 3-day follow-up. SIGNIFICANCE: Cutaneous neuromodulation using LFS via a matrix electrode has been shown to be a safe intervention for effectively reducing cancer pain in palliative care patients.

[Neuromodulation using matrix stimulation : A treatment for acute pain?] / Neuromodulation mittels Matrixstimulation : Ein Therapieansatz für akute Schmerzen?

BACKGROUND: There is currently a lack of studies that evaluate the effects of matrix electrode neuromodulation on acute pain. In this prospective and randomized cross-over study, we investigated the efficacy of 4 Hz-matrix stimulation on venipuncture-induced pain in 30 healthy subjects. METHODS: We compared two conditions of neurostimulation: in EC1 (experimental condition 1), we performed venipuncture during stimulation, with 2.5 min of prestimulation with 600 stimuli; in EC2 (experimental condition 2), the length of stimulation was 5 min, at 1200 stimuli, with subsequent venipuncture. A group with no stimulation was used as control condition. RESULTS: The EC2 group did not only show a 77% reduction in puncture pain when compared to the control group (p < 0.001; effect size [ES] d = 1.45), but also had a significant effect compared with EC1 (p < 0.001; ES d = 1.33). EC1, on the other hand, did not demonstrate a significant difference to the control group. The status of the veins was evaluated based on visibility and did not differ significantly between the conditions. CONCLUSION: The results of this study showed for the first time that pre-emptive matrix stimulation could be an effective way to reduce acute pain. The duration of stimulation seems to play a key role in the effectiveness of the neurophysiological mechanism of action. Matrix stimulation is a therapeutic intervention with very few side effects, which could, in the future, expand our pain-management options for the treatment of acute pain.

Treatment of painful radiculopathies with capsaicin 8% cutaneous patch.

BACKGROUND AND OBJECTIVE: The treatment of neuropathic pain due to low-back (lumbosacral) radiculopathies, a common source of neuropathic pain, is challenging and often requires a multimodal therapeutic approach. The capsaicin 8% patch is the first topical analgesic licensed for peripheral neuropathic pain. To evaluate this treatment, a subset of patients with painful radiculopathy (lumbar and cervical, including ventral and dorsal rami) enrolled into the multicenter, non-interventional QUEPP study (Qutenza 2 - safety and effectiveness in peripheral neuropathic pain) was analyzed. METHODS: Of the 1044 study participants, 50 were diagnosed with painful radiculopathy as only peripheral neuropathic pain syndrome and were eligible for evaluation. Patients received a single treatment (visit 1) with follow-up visits 2-5 at weeks 1-2, 4, 8 and 12. Parameters assessed at all visits included pain intensity, neuropathy symptoms and side effects. Quality of life (SF-12) and painDETECT 1 questionnaires were completed at baseline and final visit. Data was analyzed by patch application site and duration of pain. RESULTS: Topical treatment led to a significant decrease of pain intensity between weeks 1/2 and week 12 versus baseline at the application sites representing dermatomes of ventral (N = 26) and dorsal rami (N = 13) of spinal nerves. A significant decline (p ≤ .001) of numeric pain rating scale scores was observed between weeks 1/2 following patch application and the end of observation (week 12) in the overall radiculopathy group (N = 50), and the groups with either 3 months to 2 years (N = 14) or >2 years (N = 23) duration of pain. Pain relief of at least 30% was observed in 50.0%, 71.4% and 39.1% of patients in the respective groups. Four patients experienced in total seven adverse drug reactions (application site pain or pruritus). CONCLUSION: Effective neuropathic pain relief was observed after patch application within the innervation territories of both dorsal and ventral branches of the spinal nerve. Further controlled randomized trials are indicated.

[Integration of Palliative and Hospice Care Structures in the Care of Neurological Patients: Opinion of Chief Consultant Neurologists in Germany]. / Integration von Palliativ- und Hospizstrukturen in die Versorgung neurologischer Patienten ­ Meinungsbild neurologischer Chefärzte in Deutschland.

An online survey of chief neurological consultants was conducted to find out how they judged the demand for and access to palliative and hospice care (PHC) structures for their neurological patients (NP) as well as their collaboration with PHC structures. 110 of 881 chief consultants who were contacted participated in the survey. About 10 % of their NP were considered suitable for PHC. They estimated that 9 % of the deceased had died from their underlying neurological disease. The integration of PHC structures into the management of various neurological diseases was considered worthwhile but 51.9 - 78.5 % indicated that there was no or little collaboration with PHC structures. 12 % of the participants were trained in palliative care (PC). To guarantee an adequate PHC also for NP, PHC knowledge should be integrated into the curriculum and training of neurologists and the PC community should further extend its services to NP, adapting their knowledge and structures to these patients' special needs.

[Update palliative pain therapy]. / Update palliative Schmerztherapie.

Cancer pain and pain associated with non-neoplastic diseases can be associated with pain mechanisms, such as a peripheral or central sensitization or deafferentation. The clarification allows indirect conclusions about the underlying mechanisms based on clinical signs, such as allodynia or hyperalgesia. Non-opioid analgesics are the basis of cancer pain therapy according to the World Health Organization (WHO) pain ladder. In the case of severe cancer pain, treatment can be escalated directly from level 1 to level 3. Opioids are highly effective for the treatment of cancer pain even with a neuropathic component, which can occur in up to 40 % of cases as amixed pain syndrome. Coanalgesics represent a valuable therapeutic adjunct for better pain control and can address treatment of comorbidities, such as anxiety, depression and sleep disorders. When liver and/or renal function is reduced, the dosage of many drugs has to be adapted. Treatment of multimorbid or critically ill patients with opioids and antidepressants/anticonvulsants requires consideration of numerous possible pharmacodynamic and pharmacokinetic interactions.

[Dose-finding for treatment with a transdermal fentanyl patch : Titration with oral transmucosal fentanyl citrate and morphine sulfate]. / Dosisfindung zur Behandlung mit transdermalem Fentanylpflaster : Titration mit oralem, transmukosalem Fentanylcitrat und Morphinsulfat.

To date, no studies investigating titration with oral transmucosal fentanyl for the dose-finding of transdermal fentanyl treatment have been published. In an open randomized study 60 patients with chronic malignant (n = 39) or nonmalignant pain (n = 21), who required opioid therapy according to step three of the guidelines of the World Health Organization (WHO), were investigated. In two groups of 30 patients each titration with immediate release morphine (IRM) or oral transmucosal fentanyl citrate (OTFC) was undertaken. For measurement purposes the Brief Pain Inventory (BPI) and Minimal Documentation System (MIDOS) were used. After a 24-h titration phase, in which patients documented the intensity of pain, nausea, and tiredness, treatment with transdermal fentanyl was evaluated over a 10-day period by means of the necessary dose adaptation (responder ≤ 1 dose adaptation; conversion formula 1:1 [OTFC group] vs 100:1 [IRM group]).The pain reduction over the first 24 h (titration phase) did not differ significantly between the groups. The number of responders (17 OTFC vs. 21 IRM) over the 10-day period did not show any difference either. In both groups there was a significant reduction in pain intensity (p < 0.001). Over the course of the study, there were significantly more drop-outs because of adverse effects in the OTFC group than in the IRM group (8 vs 1, p = 0.028).Oral transmucosal fentanyl citrate can be applied for the titration of transdermal fentanyl, but it does not show any clinically relevant advantage. For example, the risk of side effects-induced drop-outs was greater in the present study. Whether the unnecessary opioid switching to treat chronic pain and breakthrough pain is advantageous with regard to minimizing conversion errors cannot be definitively answered within the scope of this study.

[Dyspnea, itching and depression in palliative medicine]. / Luftnot, Jucken und Depression in der Palliativmedizin.

Palliative medicine focuses on relieving burdening symptoms to improve quality of life. The most common symptoms are physical weakness, pain, loss of appetite, nausea as well as dyspnea, itching and depression. Frequently, good symptom control can be achieved using the most effective drug combination therapy or non-medicinal interventions. This article specifically addresses the physical symptoms dyspnea, itching and the psychological symptom depression.

[Pain therapy in cancer and palliative medicine]. / Tumorschmerz und palliative Schmerztherapie.

In Germany, approximately half a million people suffer from cancer pain, which is one of the most common first symptoms of tumor disease in 20-40% of the patients. The prevalence increases during the course of the disease to approximately 90% among patients in a palliative care unit. Treatment in the field of cancer pain is often provided by interdisciplinary teams of different pain or palliative care services. Due to the high availability of opioids and also, in European comparison, of a high number of specialized services in hospice and palliative care provision, Germany plays a special role next to Great Britain. There is a great need for the further development of the coordination and networking of these services within Germany, which is regulated by the Hospice and Palliative Act. The cross-sectional curricula QB 13 (palliative medicine) and QB 14 (pain medicine) were implemented in German medical faculties in order to improve integration of cancer pain management into the teaching of medical students. Research in the area of cancer pain addresses clinical topics such as the availability of opioids, but also basic research including genetic variability as a predictor for the efficacy of opioids and the neurobiology of cancer pain.

[Quantitative sensory testing]. / Quantitative sensorische Testung.

Quantitative sensory testing (QST) is a standardized and formalized set of clinical sensitivity tests based on subjective (psychophysical) methods, which depends on the cooperation of the subject being investigated. Calibrated stimuli are used to measure the perception and pain thresholds, which provide information on the presence of sensory plus or minus signs. The QST equipment presented mimics natural thermal or mechanical stimuli. The rationale is to test for patterns of functional sensory loss or gain by simultaneous assessment of both cutaneous and deep pain sensitivity. The majority of QST parameters are normally distributed only after logarithmic transformation (i.e. secondary normalization). With QST a complete somatosensory profile can be obtained within 1 h. The QST is a suitable method for characterizing the function of the somatosensory system in clinical trials and also in clinical practice as a diagnostic procedure.

Insula and sensory insular cortex and somatosensory control in patients with insular stroke.

BACKGROUND: In functional imaging studies, the insular cortex (IC) has been identified as an essential part of the processing of a whole spectrum of multimodal sensory input. However, there are no lesion studies including a sufficient number of patients, which would reinforce the functional imaging data obtained from healthy subjects. Such lesion studies should examine how damage to the IC affects sensory perception. We chose acute stroke patients with lesions affecting the IC in order to fill this gap. METHODS: A comprehensive sensory profiling by applying a quantitative sensory testing protocol was performed and a voxel-lesion behaviour mapping analysis in 24 patients with acute unilateral cortical damage was applied. RESULTS: Our data demonstrate that patients with lesions of the posterior IC have deficits in temperature perception, but did not show other sensory deficits such as hot or cold pain perception associated with specific lesion locations. CONCLUSION: Our data allow the conclusion that the posterior IC may represent the major region responsible for encoding warm and cold perception in the brain. To what extent focal IC lesions may also impair pain processing or induce post-stroke pain has to be addressed in future studies including more patients.

[Evaluation of 12 pilot projects to improve outpatient palliative care]. / Evaluation von 12 Pilotprojekten zur Verbesserung der ambulanten Palliativversorgung.

BACKGROUND: With a priority programme the German Cancer Aid supported the development of quality-assured outpatient palliative care to cover the whole country. The 12 regional pilot projects funded with the aim to improve outpatient palliative care in different models and different frameworks were concurrently monitored and evaluated. METHODS: The supported projects, starting and ending individually, documented all patients who were cared for using HOPE (Hospice and palliative care evaluation) and MIDOS (Minimal documentation system for palliative patients). Total data were analyzed for 3239 patients decriptively. In addition to the quantitative data the experiences of the projects were recorded in a number of workshops (2008, 2009, 2010, and 2012). In particular, the experiences reported in the final meeting in July 2012 were considered for this article as well as the final reports for the German Cancer Aid. RESULTS: In the quantitative evaluation 85.6% of 3239 palliative care patients had a cancer diagnosis. In all model projects the goal of a network with close cooperation of primary providers, social support, and outpatient and inpatient specialist services has been achieved. For all projects, the initial financing of the German Cancer Aid was extremely important, because contracts with health insurance funds were negotiated slowly, and could then be built on the experiences with the projects. CONCLUSION: The participants of the project-completion meeting emphasized the need to carry out a market analysis before starting palliative care organizations considering the different regional structures and target groups of patients. Education, training and continuing education programs contribute significantly to the network. A reliably funded coordination center/case management across all institutions is extremely important.

Mechanism- and experience-based strategies to optimize treatment response to the capsaicin 8% cutaneous patch in patients with localized neuropathic pain.

The capsaicin 8% cutaneous patch is an emergent new treatment option for patients with peripheral neuropathic pain. In randomized controlled clinical studies relevant pain relief for 12 weeks was achieved in about one third of patients following a single application. The first part of this paper is a review of the pathophysiology, pharmacology, and published clinical trials with the capsaicin 8% cutaneous patch. The second part reports on outcomes of an interdisciplinary expert workshop, where new treatment results of three major German pain centers were presented and reviewed with the objectives of obtaining responder rates for different pain syndromes, assessing maintenance of effect under real-life conditions, and giving recommendations for practical care. The 12 week responder rates with pain relief of ≥ 30% were comparable in patients with mononeuropathies (37.9%) and postherpetic neuralgia (38.8%). Similar responder rates were seen in a subgroup of patients with cervical spine radiculopathy and back pain (46.7%). In HIV-associated neuropathy the responder rates were high (47.8%) but lower in patients with other polyneuropathies (17.6%). Response rates were nearly identical after 1 week (46.6%) and 4 weeks (43.3) and dropped only slightly at 12 weeks (37.4%). In a subgroup of 54 patients who underwent a second treatment, efficacy was maintained. Response rates in patients with or without lidocaine pretreatment were comparable. Treatment with the capsaicin 8% cutaneous patch was generally safe and well tolerated. The workshop panel recommended further investigation of opportunities to improve the application procedure and to perform studies on the skin penetration and distribution of capsaicin. A modified quantitative sensory testing (QST) should be developed for clinical practice in order to better understand the correlation of sensory profiles and response to capsaicin treatment.

[Pain management in palliative care. Current aspects of medicinal therapy]. / Palliative Schmerztherapie. Aktuelle Aspekte der Arzneimitteltherapie.

Palliative care patients do not only suffer from cancer pain but also from painful muscle spasticity due to multiple sclerosis, amyotrophic lateral sclerosis, after stroke or due to dementia if damage of the pyramidal motor system is present. Centrally active muscle relaxants can be helpful also when used as coanalgesics for cancer pain. In addition to opioids other coanalgesics, such as tricyclic antidepressants or serotonin/noradrenalin reuptake inhibitors as well as anticonvulsants (sodium channel and calcium channel blockers) can be helpful if neuropathic cancer pain is present. Idiopathic Parkinsonism or multiple system atrophy leads more to a painful rigor and pain control should be supported here by optimal adjustment of L-DOPA or DOPA agonist therapy. However, pain treatment should always address the psychological, social and spiritual demands of the patient.

[Glucocorticoids and androgens for treatment of tiredness and weakness in palliative care patients : a systematic review]. / Glukokortikoide und androgene zur behandlung von müdigkeit und schwäche bei palliativpatienten : eine systematische übersichtsarbeit.

BACKGROUND: The therapy of tiredness, weakness and fatigue in palliative care patients is of growing interest. Glucocorticoids and androgens are habitually mentioned drugs for treatment. In this review evidence for glucocorticoids and androgens for these indications in palliative care patients are presented. MATERIALS AND METHODS: A systematic search of PubMed and Embase for studies on glucocorticoids and androgens for fatigue, asthenia, sedation, tiredness, weakness, exhaustion, cachexia, drowsiness and wasting in palliative care was carried out in August 2011. Furthermore, the Cochrane Library, references from the literature and leading textbooks were also searched. Study information was entered in a standardized extraction sheet. By a categorization of studies five endpoints were distinguished: fatigue, strength/weakness, tiredness, well being/quality of life and energy/activity/performance. RESULTS: A total of 11 controlled studies with glucocorticoids and 13 controlled studies with androgens were included. In addition four uncontrolled studies, two case series and two surveys with glucocorticoids as well as six uncontrolled studies and one case series with androgen treatment were analyzed. All controlled trials of glucocorticoids were performed in cancer patients and all but one controlled trial of androgens in patients with HIV/AIDS. Glucocorticoids improved quality of life but results for changes of fatigue and weakness were inconsistent. Tiredness and energy were not improved. Androgens had a positive effect on fatigue and quality of life and showed variable effects on weakness. Androgens did not improve energy. Side effects were frequently documented but only rarely resulted in discontinuation of therapy. CONCLUSION: With the existing evidence no general recommendation for glucocorticoid and androgen use in tiredness and weakness in palliative care patients can be given; however, glucocorticoids in cancer patients and androgens in HIV positive-patients can be used in an individual trial for improving patient quality of life. The use in patients suffering from other disease entities should be evaluated in randomized controlled trials with a similar setting. The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental").

[Methods and development of therapy recommendations for symptom control in palliative medicine]. / Methodik und entwicklung von therapieempfehlungen zur symptomkontrolle in der palliativmedizin.

The Drug Commission of the German Medical Association has decided to develop treatment guidelines for palliative care. A series of systematic reviews was commissioned to evaluate the evidence for interventions of common symptoms that burden patients and care givers. A common methodology for all reviews is described in this paper. The methodology was based on the work of the European Palliative Care Research Collaborative. Standardized search strategies were identified in PubMed and Embase and these templates were then adapted by the authors of the reviews according to their needs. The template included the target group (patients and disease entities), indications (symptoms) and interventions (medicines and classes of medicines). Target groups included search terms on palliative or hospice care, cancer, neurodegenerative diseases, HIV/AIDS as well as cardiac and pulmonary failure. The number of relevant hits was surveyed in the first 40 hits in some exemplary searches. This was used for fine tuning the search templates and to optimize the search strategy in order to achieve the highest possible yield with the minimum possible effort. The review series was performed using this search strategy. Every review graded the quality of the included evidence following categories of the Drug Commission of the German Medical Association. Based on these results and recommendations the treatment guidelines will be formulated which will offer concise and evidence-based guidelines for general palliative medicine, offering primary care givers guidance for adequate palliative care in severely ill and dying patients. The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental").