PAIN2.0: study protocol for a multicentre randomised controlled trial to evaluate the efficacy of a 10-week outpatient interdisciplinary multimodal pain therapy to manage recurrent pain for patients with risk factors of developing chronic pain in Germany.

BACKGROUND: Up to 27% of the German population suffers from recurrent or persistent pain (lasting more than three months). Therefore, prevention of chronic pain is one major object of pain management interventions. The aim of this nationwide, multicentre, randomised controlled trial is to evaluate the efficacy of a 10-week ambulatory (outpatient) interdisciplinary multimodal pain therapy (A-IMPT) for patients with recurrent pain and at risk of developing chronic pain. This project was initiated by the German Pain Society (Deutsche Schmerzgesellschaft e.V.) and the public health insurance provider BARMER. It is currently funded by the German Innovation Fund (01NVF20023). The study PAIN2.0 focuses on reducing pain intensity and pain-related disability and investigates whether this intervention can improve physical activity, psychological well-being, and health literacy. METHODS: PAIN2.0 is designed as a multicentre 1:1 randomised controlled trial with two parallel groups (randomisation at the patient level, planned N = 1094, duration of study participation 12 months, implemented by 22 health care facilities nationwide). After 6 months, patients within the control group also receive the intervention. The primary outcomes are pain intensity and pain-related impairment, measured as Characteristic Pain Intensity (PI) and Disability Score (DS) (Von Korff), as well as patient-related satisfaction with the intervention. Secondary outcomes are the number of sick leave days, sickness allowance, treatment costs, psychological distress, health-related quality of life, and catastrophizing. The effects of the intervention will be analysed by a parallel-group comparison between the intervention and control groups. In addition, the long-term effects within the intervention group will be observed and a pre-post comparison of the control group before and after the intervention will be performed. DISCUSSION: Recurrent or persistent pain is common in the German population and causes high costs for patients and society. The A-IMPT aims to improve pain and pain-related impairments in pain patients at risk of chronification, thereby reducing the risk of developing chronic pain with its high socioeconomic burden. This new therapy could easily be integrated into existing therapy programs if positively evaluated. TRIAL REGISTRATION: The trial PAIN2.0 has been registered in the German Clinical Trials Register (DRKS) since 21/11/2022 with the ID DRKS00030773 .

Gadolinium contrast agents: dermal deposits and potential effects on epidermal small nerve fibers.

Small fiber neuropathy (SFN) affects unmyelinated and thinly myelinated nerve fibers causing neuropathic pain with distal distribution and autonomic symptoms. In idiopathic SFN (iSFN), 30% of the cases, the underlying aetiology remains unknown. Gadolinium (Gd)-based contrast agents (GBCA) are widely used in magnetic resonance imaging (MRI). However, side-effects including musculoskeletal disorders and burning skin sensations were reported. We investigated if dermal Gd deposits are more prevalent in iSFN patients exposed to GBCAs, and if dermal nerve fiber density and clinical parameters are likewise affected. 28 patients (19 females) with confirmed or no GBCA exposure were recruited in three German neuromuscular centers. ISFN was confirmed by clinical, neurophysiological, laboratory and genetic investigations. Six volunteers (two females) served as controls. Distal leg skin biopsies were obtained according to European recommendations. In these samples Gd was quantified by elemental bioimaging and intraepidermal nerve fibers (IENF) density via immunofluorescence analysis. Pain phenotyping was performed in all patients, quantitative sensory testing (QST) only in a subset (15 patients; 54%). All patients reported neuropathic pain, described as burning (n = 17), jabbing (n = 16) and hot (n = 11) and five QST scores were significantly altered. Compared to an equal distribution significantly more patients reported GBCA exposures (82%), while 18% confirmed no exposures. Compared to unexposed patients/controls significantly increased Gd deposits and lower z-scores of the IENF density were confirmed in exposed patients. QST scores and pain characteristics were not affected. This study suggests that GBCA exposure might alter IENF density in iSFN patients. Our results pave the road for further studies investigating the possible role of GBCA in small fiber damage, but more investigations and larger samples are needed to draw firm conclusions.

Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies - (lessons learned from) a prospective study.

This prospective cohort study aimed to characterise the impact of oxaliplatin-based chemotherapy and its neurotoxic side effects (i.e., chemotherapy-induced neuropathy) on functional fall-risk and falls. Twenty chemotherapy-naïve participants (mean age, 59 years; 16 males) were consecutively included. A multimodal fall risk assessment was performed at four time points within 6 months. Polyneuropathy was assessed using the Neurologic Disability Scale; the fall risk was assessed by functional tests (Tinetti Test, Chair-Rising Test, and Timed up and Go Test). Patient-reported outcomes comprised the Hospitality Anxiety and Depression Scale (HADS), the Falls Efficacy Scale - International (FES-I) to assess the fear of falling, and the Physical Activity for the Elderly (PASE) questionnaire. Three falls occurred during the study. All fallen participants had a high fall risk-index (≥4 more risk factors) compared to only 30% of the non-fallen participants (p = 0.03) and suffered more frequently from pre-existing mild polyneuropathy (p = 0.049). Study discontinuation (n = 12) was associated with a higher rate of polypharmacy (p = 0.045), anxiety (HADS-A, p = 0.03), and specific fear of falling (FES-I, p = 0.025). In contrast, study completers (n = 8) reported an improvement in physical activity (PASE) (p = 0.018). In summary, pre-existing fall-risk factors impacted more falls than chemotherapy. A fall risk index offers a time-efficient screening option in an outpatient oncological setting.

Somatosensory and Gustatory Profiling in the Orofacial Region.

Quantitative sensory testing (QST) is a standard procedure in medicine to describe sensory patterns in various pathologies. The aim of this prospective clinical study was to define reference values of the trigeminal nerve (V3), including taste qualities, to create a compatibility for sensory loss or gain in pathologies. Fifty-one patients were included, and a standardized testing battery with 11 QST parameters according to the German Research Network on Neuropathic Pain (DFNS) was applied complemented by quantitative gustatory assessments. Significant somatosensory differences were found between the test sites (MDT at the chin, WDT at the lower lip) but no effect was detected for gender, age, and between body types. Taste sensitivity was dependent on concentration, gender (females being more sensitive) and increasing age (for bitter and sour taste). We provide reference values for somatosensory and gustatory testing of the facial area. Our data facilitate the detection of neurosensory abnormalities in the orofacial region. This might also serve as a control setting for COVID-19.

Sympathetic and sensory nerve fiber function in multiple system atrophy and idiopathic Parkinson's disease.

OBJECTIVE: To explore small fiber somatosensory and sympathetic function in PD and MSA. METHODS: We recruited 20 PD patients (7 women, median age 65.5 years; IQR 54.75-70.0), 10 MSA patients (4 women; median age 68 years; IQR 66.25-74.0), and 10 healthy subjects (HC; 4 women, median age 68; IQR 59.0-71.0 years). Autonomic testing included forehead cooling, intradermal microdialysis of norepinephrine (NE; 10-5; 10-6; 10-7; and 10-8), and orthostatic hypotension (OH); somatosensory testing included quantitative sensory testing (QST) according to the protocol of the German Research Network on Neuropathic Pain (DFNS). RESULTS: OH occurred more frequently in PD (p = 0.018) and MSA (p = 0.002) compared to HC. Vasoconstriction responses were stronger in PD compared to MSA during forehead cooling (p = 0.044) and microdialysis of physiologically concentrated NE solutions (10-7; 10-8; p = 0.017). PD and MSA had impaired cold (PD: p < 0.01; MSA: p < 0.05) and warm detection thresholds (PD and MSA, both p < 0.05). The mechanical detection threshold was higher in PD (p < 0.01). Conversely, mechanical pain thresholds were decreased in PD and MSA (both p < 0.001), indicating mechanical hyperalgesia. CONCLUSION: In contrast to MSA, we found evidence of peripheral adrenoreceptor hypersensitivity in PD, probably caused by peripheral sympathetic denervation. Sensory testing revealed peripheral neuropathy and central pain sensitization in PD and MSA. Jointly, our data demonstrate autonomic and somatosensory dysfunction in PD and MSA.

Chance or challenge, spoilt for choice? New recommendations on diagnostic and therapeutic considerations in hereditary transthyretin amyloidosis with polyneuropathy: the German/Austrian position and review of the literature.

Hereditary transthyretin amyloidosis is caused by pathogenic variants (ATTRv) in the TTR gene. Alongside cardiac dysfunction, the disease typically manifests with a severely progressive sensorimotor and autonomic polyneuropathy. Three different drugs, tafamidis, patisiran, and inotersen, are approved in several countries, including the European Union and the United States of America. By stabilizing the TTR protein or degrading its mRNA, all types of treatment aim at preventing amyloid deposition and stopping the otherwise fatal course. Therefore, it is of utmost importance to recognize both onset and progression of neuropathy as early as possible. To establish recommendations for diagnostic and therapeutic procedures in the follow-up of both pre-symptomatic mutation carriers and patients with manifest ATTRv amyloidosis with polyneuropathy, German and Austrian experts elaborated a harmonized position. This paper is further based on a systematic review of the literature. Potential challenges in the early recognition of disease onset and progression are the clinical heterogeneity and the subjectivity of sensory and autonomic symptoms. Progression cannot be defined by a single test or score alone but has to be evaluated considering various disease aspects and their dynamics over time. The first-line therapy should be chosen based on individual symptom constellations and contra-indications. If symptoms worsen, this should promptly implicate to consider optimizing treatment. Due to the rareness and variability of ATTRv amyloidosis, the clinical course is most importantly directive in doubtful cases. Therefore, a systematic follow-up at an experienced center is crucial to identify progression and reassure patients and carriers.

Heterogeneous presentation of caspr2 antibody-associated peripheral neuropathy - A case series.

Contactin-associated protein 2-like (caspr2) antibodies have been discovered recently. Since then a multitude of patients with caspr2 antibodies presenting with different neurological symptoms have been reported. Here, we describe three patients with caspr2 antibodies with different types of pain/no pain in combination with peripheral neuropathy. The first patient, a 33-year-old woman, presented with erythromelalgia-like pain and autonomic symptoms; the second patient, a 58-year-old man, with paresthesia and pain while walking together with signs of peripheral motor neuron hyperexcitability in combination with optic neuritis, and the third patient, a 74-year-old man, without any pain but with polyneuropathy and encephalopathy. These cases illustrate the spectrum of symptoms in anti-caspr2 diseases. The pain in such cases can be treated causally.

Follow-up in transthyretin familial amyloid polyneuropathy: Useful investigations.

Patients with transthyretin amyloid polyneuropathy (TTR-FAP) and asymptomatic mutation-carriers have to be regularly followed-up in order to identify disease progression and the time point for starting or modifying therapy. In this case series we describe the potential suitability of different variables as progression markers. We retrospectively analyzed the follow-up charts of 10 TTR-FAP patients. Clinical examination included the Neuropathy Impairment Score of Lower Limb (NIS-LL), temperature perception thresholds, nerve conduction and autonomic function tests. The NIS-LL had the greatest value for a sensitive and correct follow-up for all TTR-FAP stages. All other examinations provided useful additional information but they were either less suited for advanced TTR-FAP, or had a higher test-retest variability. The results of this study provide preliminary evidence that a good clinical investigation is mandatory in TTR-FAP follow-up. Simple neuropathy scores like the NIS-LL might be as useful as technical investigations for TTR-FAP follow-up.

Somatosensory profiles in acute herpes zoster and predictors of postherpetic neuralgia.

This prospective cohort study aimed to characterize the sensory profile during acute herpes zoster (AHZ) and to explore sensory signs as well as physical and psychosocial health as predictors for postherpetic neuralgia (PHN). Results of quantitative sensory testing of 74 patients with AHZ at the affected site and at the distant contralateral control site were compared to a healthy control group. Pain characteristics (Neuropathic Pain and Symptom Inventory and SES), physical functioning, and psychosocial health aspects (Pain Disability Index, SF-36, and STAI) were assessed by questionnaires. Patients with PHN (n = 13) at 6-month follow-up were compared to those without PHN (n = 45). Sensory signs at the affected site were thermal and vibratory hypesthesia, dynamic mechanical allodynia (DMA), pressure hyperalgesia, and high wind-up (18%-29%), as well as paradoxical heat sensations and pinprick hypalgesia (13.5%). The unaffected control site exhibited thermal and vibratory hypesthesia, DMA, and pressure hyperalgesia. Dynamic mechanical allodynia and pinprick hypalgesia were mutually exclusive. Postherpetic neuralgia was associated with DMA (38.5% vs 6.7%; P = 0.010) and vibratory hypesthesia (38.5% vs 11.1%; P = 0.036) at the control site, with mechanical gain and/or loss combined with normal thermal detection (affected site: 69.2% vs 31.1%; P = 0.023; control site: 53.8% vs 15.5%; P = 0.009). Pain Disability Index (P = 0.036) and SES affective pain perception scores (P = 0.031) were over 50% higher, and 6 of 8 SF-36 subscores were over 50% lower (P < 0.045) in PHN. Sensory profiles in AHZ indicate deafferentation and central but not peripheral sensitization. Sensory signs at distant body sites, strong affective pain perception, as well as reduced quality of life and physical functioning in the acute phase may reflect risk factors for the transition to PHN.

Pilot field testing of the chronic pain classification for ICD-11: the results of ecological coding.

BACKGROUND: A task force of the International Association for the Study of Pain (IASP) has developed a classification of chronic pain for the ICD-11 consisting of seven major categories. The objective was to test whether the proposed categories were exhaustive and mutually exclusive. In addition, the perceived utility of the diagnoses and the raters' subjective diagnostic certainty were to be assessed. METHODS: Five independent pain centers in three continents coded 507 consecutive patients. The raters received the definitions for the main diagnostic categories of the proposed classification and were asked to allocate diagnostic categories to each patient. In addition, they were asked to indicate how useful they judged the diagnosis to be from 0 (not at all) to 3 (completely) and how confident they were in their category allocation. RESULTS: The two largest groups of patients were coded as either chronic primary pain or chronic secondary musculoskeletal pain. Of the 507 patients coded, 3.0% had chronic pain not fitting any of the proposed categories (97% exhaustiveness), 20.1% received more than one diagnosis. After adjusting for double coding due to technical reasons, 2.0% of cases remained (98% uniqueness). The mean perceived utility was 1.9 ± 1.0, the mean diagnostic confidence was 2.0 ± 1.0. CONCLUSIONS: The categories proved exhaustive with few cases being classified as unspecified chronic pain, and they showed themselves to be mutually exclusive. The categories were regarded as useful with particularly high ratings for the newly introduced categories (chronic cancer-related pain among others). The confidence in allocating the diagnoses was good although no training regarding the ICD-11 categories had been possible at this stage of the development.

Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study.

Liver transplantation (LT) is the first-line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated. The cohort included 24 FAP- (11 Val30Met, 13 nonVal30Met) and 23 DR-patients. DR symptoms referred to post-DLT only, while those of FAP patients were both pre- and post-transplantation. Symptoms of TTR-amyloidosis in Val30Met and Non-Val30Met patients pre- and post-LT were similarly distributed. Biopsy-proven de novo amyloidosis occurred in 4/23 DR after a mean observation of 10 years. Analysis for manifestations of amyloidosis only included patients with available 5-year follow-up data (n = 13 FAP, n = 12 DR). Compared to Val30Met FAP patients pre-LT, Val30Met DR patients had better NCV (P = 0.04) and HRV (P = 0.015). In the Non-Val30Met group no differences were found between DR and FAP patients pre-LT. TTR-amyloidosis symptoms showed no differences in FAP patients pre- and 5 years post-LT, irrespective of Val30Met status. In DR patients, de novo amyloidosis occurred earlier than expected. Therefore, recipients for DLT need to be carefully selected and followed.

Transthyretin familial amyloid polyneuropathy (TTR-FAP): Parameters for early diagnosis.

Background: Familial transthyretin amyloidosis is a life-threatening disease presenting with sensorimotor and autonomic polyneuropathy. Delayed diagnosis has a detrimental effect on treatment and prognosis. To facilitate diagnosis, we analyzed data patterns of patients with transthyretin familial amyloid polyneuropathy (TTR-FAP) and compared them to polyneuropathies of different etiology for clinical and electrophysiological discriminators. Methods: Twenty-four patients with TTR-FAP and 48 patients with diabetic polyneuropathy (dPNP) were investigated (neurological impairment score NIS; neurological disability score NDS) in a cross-sectional design. Both groups were matched for gender and presence of pain. Quantitative sensory testing (QST), sympathetic skin response (SSR), heart rate variability (HRV), and nerve conduction studies (NCV) were performed. Both groups were compared using univariate analysis. In a stepwise discriminant analysis, discriminators between both neuropathies were identified. These discriminators were validated comparing TTR-FAP patients with a cohort of patients with chemotherapy-induced polyneuropathy (CIN) and chronic inflammatory demyelinating neuropathy (CIDP). Results: TTR-FAP patients scored higher in NDS and NIS and had impaired cold detection (CDT, p = .024), cold-warm discrimination (TSL, p = .019) and mechanical hyperalgesia (MPT, p = .029) at the hands, SSR (upper limb, p = .022) HRV and ulnar and sural NCS (all p < .05) were more affected in TTR-FAP. Ulnar nerve sensory NCV, CDT, and the MPT but not the other parameters discriminated TTR-FAP from dPNP (82% of cases), from CIN (86.7%) and from CIDP (68%; only ulnar sNCV). Conclusion: Low ulnar SNCV, impaired cold perception, and mechanical hyperalgesia at the hands seem to characterize TTR-FAP and might help to differentiate from other polyneuropathies.

Polyneuropathies.

BACKGROUND: Polyneuropathies (peripheral neuropathies) are the most common type of disorder of the peripheral nervous system in adults, and specifically in the elderly, with an estimated prevalence of 5-8%, depending on age. The options for treatment depend on the cause, which should therefore be identified as precisely as possible by an appropriate diagnostic evaluation. METHODS: This review is based on the current guidelines and on large-scale cohort studies and randomized, controlled trials published from 2000 to 2017, with an emphasis on non-hereditary types of polyneuropathy, that were retrieved by a selective search in PubMed. RESULTS: Diabetes is the most common cause of polyneuropathy in Europe and North America. Alcohol-associated polyneuropathy has a prevalence of 22-66% among persons with chronic alcoholism. Because of the increasing prevalence of malignant disease and the use of new chemotherapeutic drugs, chemotherapy-induced neuropathies (CIN) have gained in clinical importance; their prevalence is often stated to be 30-40%, with high variation depending on the drug(s) and treatment regimen used. Polyneuropathy can also arise from genetic causes or as a consequence of vitamin deficiency or overdose, exposure to toxic substances and drugs, and a variety of immunological processes. About half of all cases of polyneu - ropathy are associated with pain. Neuropathic pain can be treated symptomatically with medication. Exercise, physiotherapy, and ergotherapy can also be beneficial, depending on the patient's symptoms and functional deficits. CONCLUSION: A timely diagnosis of the cause of polyneuropathy is a prerequisite for the initiation of appropriate specific treatment. Patients with severe neuropathy of unidentified cause should be referred to a specialized center for a thorough diagnostic evaluation.

A critical evaluation of validity and utility of translational imaging in pain and analgesia: Utilizing functional imaging to enhance the process.

Assessing clinical pain and metrics related to function or quality of life predominantly relies on patient reported subjective measures. These outcome measures are generally not applicable to the preclinical setting where early signs pointing to analgesic value of a therapy are sought, thus introducing difficulties in animal to human translation in pain research. Evaluating brain function in patients and respective animal model(s) has the potential to characterize mechanisms associated with pain or pain-related phenotypes and thereby provide a means of laboratory to clinic translation. This review summarizes the progress made towards understanding of brain function in clinical and preclinical pain states elucidated using an imaging approach as well as the current level of validity of translational pain imaging. We hypothesize that neuroimaging can describe the central representation of pain or pain phenotypes and yields a basis for the development and selection of clinically relevant animal assays. This approach may increase the probability of finding meaningful new analgesics that can help satisfy the significant unmet medical needs of patients.

Interaction of calcitonin gene related peptide (CGRP) and substance P (SP) in human skin.

Calcitonin gene related peptide (CGRP) and substance P (SP) are neuropeptides that are simultaneously released from nociceptive C-fibers. CGRP is a potent vasodilator, inducing a long-lasting increase in superficial skin blood flow, whereas SP induces only a brief vasodilation but a significant plasma extravasation. CGRP and SP may play important roles in the pathophysiology of various pain states but little is known about their interaction. Different concentrations of SP (ranging from 10-5M to 10-9M) were applied to the volar forearm of 24 healthy subjects via dermal microdialysis. SP was applied either alone or in combination with CGRP10-9M and CGRP 10-6M. As expected, SP induced a transient increase in skin blood flow that decayed shortly after application. This transient blood flow peak was blunted with co-application of CGRP 10-9M and inhibited with co-application of CGRP10-6M. SP alone induced plasma protein extravasation (PPE). However, when CGRP10-6M was added, the PPE significantly increased. Our results demonstrate a complex interaction of the neuropeptides CGRP and SP. CGRP10-6M prevented SP-induced early vasodilation but augmented SP-induced PPE. These interactions might explain why vascular symptoms in chronic pain can differ strikingly between individuals.

Anosognosia for obvious visual field defects in stroke patients.

Patients with anosognosia for visual field defect (AVFD) fail to recognize consciously their visual field defect. There is still unclarity whether specific neural correlates are associated with AVFD. We studied AVFD in 54 patients with acute stroke and a visual field defect. Nineteen percent of this unselected sample showed AVFD. By using modern voxelwise lesion-behaviour mapping techniques we found an association between AVFD and parts of the lingual gyrus, the cuneus as well as the posterior cingulate and corpus callosum. Damage to these regions appears to induce unawareness of visual field defects and thus may play a significant role for conscious visual perception.