Induction of long-term synaptic depression (LTD) is proposed as a treatment mechanism for chronic pain but remains untested in clinical populations. Two interlinked studies; (1) A patient-assessor blinded, randomised, sham-controlled clinical trial and (2) an open-label mechanistic study, sought to examine therapeutic LTD for persons with chronic peripheral nerve injury pain.(1) Patients were randomised using a concealed, computer-generated schedule to either active or sham non-invasive low-frequency nerve stimulation (LFS), for 3 months (minimum 10 min/day). The primary outcome was average pain intensity  recorded over 1 week, at 3 months, compared between study groups. (2) On trial completion, consenting subjects entered a mechanistic study assessing somatosensory changes in response to LFS.(1) 76 patients were randomised (38 per group), with 65  included in the intention to treat analysis. The primary outcome was not significant, pain scores were 0.3 units lower in active group  giving an effect size of 0.19 (Cohen’s D). Two non-device related serious adverse events were reported. (2) In the mechanistic study (n = 19) primary outcomes of mechanical pain sensitivity (p = 0.006) and dynamic mechanical allodynia (p = 0.043) significantly improved indicating reduced mechanical hyperalgesia.Results from the RCT failed to reach significance. Results from the mechanistic study provide new evidence for effective induction of LTD in a clinical population. Taken together results add to mechanistic understanding of LTD and help inform future study design and approaches to treatment. Trial registration ISRCTN53432663. Neuropathic pain can arise either peripherally or centrally as a direct consequence of a lesion or disease affecting the somatosensory system. Classification of neuropathic pain syndromes, using quantitative sensory testing (QST) has defined patterns of loss or gain of function across sensory modalities (‘somatosensory profiles’) which may reflect underlying pain generating mechanisms . NeuropaIn rodent models, reversal of nerve-injury induced LTP is achieved through low frequency peripheral nerve stimulation which induces the counterbalancing process of ‘long term depression’ (LTD) where central nociceptive synaptic connections become actively weakened ; low freIn clinical trials, surgical forms of peripheral nerve stimulation do not consistently utilise low frequency stimulation , whilst The current work sought to validate whether LTD can be induced within this clinical population employing an LFS technique and explore the potential efficacy of a non-invasive approach only to elicit LTD-related pain suppression. To do this, we conducted two interlinked studies. The research describes a parallel group, double blinded, sham-controlled randomised trial and an open label mechanistic study assessing psychophysical parameters pre and post low frequency stimulation. We hypothesised that for the open label mechanistic study a significant reduction (p =  < 0.05) in mechanical pain sensitivity and dynamic mechanical allodynia would be observed following low-frequency stimulation, and that within the RCT a significant difference (p =  < 0.05) in terms pain reduction in favour of the active treatment would be seen.A single site parallel group, double blinded, sham randomised controlled trial (RCT) of external non-invasive peripheral electrical nerve stimulation (ENPENS), designed to assess the efficacy of ENPENS versus sham in patients with chronic pain following peripheral nerve injury. Patients were randomised to receive either active or control treatment and continued treatment for a period of 3 months (main treatment phase). As a further retention and recruitment aid, following completion of the main treatment phase patients were offered an optional cross over or treatment extension (3 months).Screened subjects who met the inclusion/exclusion criteria either before or after completion of the extension/swap period were invited to participate in a further open label mechanistic study assessing psychophysical parameters pre and post low frequency stimulation to validate LTD as a working mechanism within a clinical sample.Suitable patients appearing to fulfil inclusion/exclusion criteria identified from the centre’s pain clinics received a pre-screening telephone assessment. Patients then attended a screening appointment where written informed consent was obtained by the study PI. Separate written consent was obtained for the mechanistic study.Patients were eligible if they were aged 18 or older and had definite or probable pain post nerve injury of ≥ 12 months duration . They exPatients were excluded if they had absolute numbness in the affected area, had known treatment contraindications, implantable devices for the same condition, unstable pain intensity of pain medications in the 6 weeks prior to the trial, had diagnosed psychiatric or mental health disorder or other health conditions/pain which in the opinion of the investigators would make the trial unsuitable, or were unable to comply with the study protocol. Additionally, patients were required to stop any medications that numb affected areas prior to the study to enable stimulation of the peripheral nerves. Lidocaine patches 2 weeks prior, Capsaicin treatments  4 months prior to stimulation to allow nerve endings to grow back. Patients were requested not to commence any new medications/ treatments that may confuse evaluation of treatment efficacy. All prescribed and non-prescribed treatments were recorded throughout.The criteria were the same for both studies with the exception that brushstroke allodynia (≥ 3/10 NRS) was not required for the mechanistic study. This study sought to demonstrate a reduction in mechanical hypersensitivity and although brushstroke allodynia is often a feature of this (exhibited by 15/19 patients) significant mechanical hypersensitivity can also exist without the presence of documented brushstroke allodynia .Once consented patients were randomised to either active or sham treatment. The study trial manager or PI randomised patients using an independent online randomisation service that employed a concealed 1:1 allocation schedule and varying block sizes of 2 and 4. Trial nurses and patients were blinded to treatment allocation and were informed that that the purpose of the trial was to compare two types of stimulation ‘Pen’ and ‘Flat’. They were further informed that efficacy was not related to strength of stimulus but rather determined by the electrical field (see active and sham device). Following randomisation assignment, trial nurses were provided with the appropriate stimulation device to issue to the patient. Randomisation was not employed for the mechanistic study.The study was conducted at a supra-regional UK national health services (NHS) neurology and neurosurgery hospital. The study was registered on the ISRCTN registry, registry number: ISRCTN53432663. The full protocol was published before initiation of the trial . The triThe RCT primary objective was to establish whether ENPENS treatment versus sham treatment was effective in reducing pain for people with long-standing neuropathic pain following peripheral nerve injury, as measured by change in pain intensity following 3 months of treatment. Secondary objectives were to assess the benefits associated with treatment to other commonly affected areas such as quality of life, function, mood, self-efficacy (confidence to perform abilities in the presence of pain), reduction of allodynia in the areas of pain, and symptom report. The primary objective for the mechanistic open label study was to establish whether LFS was associated in reduction of enhanced pain-responsiveness in a clinical population, as measured by change in measured sensory features of clinically enhanced pain responsiveness. We hypothesised that within the RCT a significant difference (p =  < 0.05) in terms pain reduction, would be observed between groups in favour of the active treatment. Whilst for the open label mechanistic study a significant reduction (p =  < 0.05) in mechanical pain sensitivity and dynamic mechanical allodynia would be observed following low-frequency stimulation.Sample size calculations were conservatively based on detection of a between-group difference of 1.5 following previous observational study data that had shown a mean treatment associated pain reduction of 2.8 units. The standard deviation of the outcome was assumed to be as per this data, 1.9 units . A corre2 square adhesive electrode and parameters of 2 Hz, 0.1 ms, ≤ 6 mA . The electrode and parameter combination created a perceivable, low current density not eliciting LTD [Low frequency nerve stimulation through a transcutaneous-applied, small spherical electrode that induces high current density is a long-established method to localize peripheral nerves for nerve blocks . Active ting LTD . Electroting LTD , 10. To Once able to demonstrate independent use of the device, patients were loaned a stimulator for 3 months, stimulating for a minimum of 10 min daily, at a mildly painful but not intolerable amplitude. Patients determined the amplitude, frequency, and timings of stimulation. Weekly telephone calls during the main treatment phase recorded treatment compliance and health care utilization.At baseline, the area of mechanical hyperalgesia was mapped using a pinprick stimulus of 256 mN along eight equally spaced tracks originating from the epicentre of pain. Then, a circular intervention array of 10 punctate electrodes (each 250 µm diameter), designed to preferentially activate small diameter epidermal nerve fibres (5), was placed over the epicentre of the pain. This electrode delivers electrical pulses using a constant current stimulator . Baseline QST was then performed on areas directly adjacent the intervention array-electrode to obtain a comprehensive somatosensory profile, using the standardised German Research Network quantitative sensory testing (DFNS) protocol . As partRCT outcomes were completed by patients and collected by trial nurses. Outcome questionnaires were scored, and all data entered onto a computer by a technical assistant independent to the trial. Data analysis was conducted by the unblinded statistician after data lock.The RCT primary study endpoint was the average 24 h pain intensity recorded daily on an 11-point  numerical rating scale (NRS), averaged over the last 7 days of the three-month treatment phase. At least 1 daily score was required.The co-primary outcomes were change in intensity of mechanical pain sensitivity and dynamic mechanical allodynia following LFS, normalised to baseline. The secondary outcome was the change in mechanical hyperalgesia area following LFS. Spontaneous post-test pain was not measured as this parameter was considered confounded by the lengthy examination protocol.Brief pain inventory interference subscale (BPI-I)  .EuroQol EQ-5D-5L generic measure of health status. The EQ-5D-5L has two components, a summary index (utility), and the EQ visual analogue scale (EQ-VAS),  .Text within brackets indicates what each measure was intended to capture.Hospital anxiety and depression scale  .Pain self-efficacy questionnaire (perceived confidence to function despite pain) .Worst pain using BPI (range of pain intensity) .Dynamic mechanical allodynia determined by manual mapping  .Neuropathic pain symptom inventory (NPSI)  .Outcomes were recorded at baseline, treatment completion and on completion of the optional treatment extension/swap. Secondary and exploratory endpoints were scores following end of 3-month treatment phase. Treatment phase patient diaries captured daily pain intensities and treatment frequencies.Patient perceived global impression of change (PGIC) .Telephone interview—qualitative exploration of ‘active’ treatment experience in a proportion of patients.Perception regarding treatment allocation. Patients were asked if they felt they had been assigned to a more or less effective stimulation.At every patient contact, safety adverse events (SAEs) and serious adverse events (SARs) were recorded.The primary study analysis was intention to treat (ITT) based on all randomized, eligible patients with outcome measures available at the end of the study. For the primary outcome, the primary endpoint was compared between groups by Analysis of Covariance (ANCOVA) using baseline scores as the covariate. In a secondary analysis of the primary outcome  the proportion of patients in each arm that achieved distinct outcomes  were computed. The minimally clinically important difference (MCID) was defined as ≥ 2 points . No straEquivalent methods were used for those secondary and exploratory outcomes measured on continuous scales. For analysis of ordinal outcomes, the Mann–Whitney test was used. MCID was calculated for all further outcomes as follows based on the available literature: BPI-I 2-point reduction, EQ-5D-5L VAS 11 points increase, utility 0.145 increase, HADS 4 points reduction plus movement between severity categories, PSEQ increase of 7 + points plus movement between severity categories, BPI worst pain 3-point decrease, 20% reduction in surface area of allodynia , 29–32. Details of the healthcare resource use and cost analysis are described in the published protocol . A pre-pQST values  were z-transformed using the mean and standard deviation (SD) of the healthy control normative data for age, gender, and body location . Z-scoreWithin the RCT 278 patients were screened between January 26, 2017–July 11, 2019, 76 patients were randomised to treatment (38 per group), and 65/76 (86%) provided end of treatment outcomes and were included in the primary study efficacy analysis . On completion of the RCT treatment phase 42/65 participated in the optional treatment extension/ swap phase. Participant flow and reasons for withdrawal are detailed in Fig. Seventeen of the 76 patients randomised entered the mechanistic study, along with four patients excluded from the RCT study due to low mechanical allodynia scores ≤ 3 numerical rating scale (NRS). Two of these 21 patients (both RCT participants) were unable to tolerate the electrical stimulation at × 5 EDT and withdrew, therefore 19 patients completed mechanistic testing. Fifteen of these had been randomised in the RCT study, of which five attended directly after the main treatment phase, ten after the extension/swap.Patient demographic and baseline characteristics were broadly similar between the active and sham arms Table .Table 1PIn the mechanistic study, full demographic data was not available for the four patients who had not participated in the RCT study, i.e., was available for 15/19 participants (Table Baseline quantitative sensory (QST) testing using DFNS protocol , was obtMechanistic study outcomes The co-primary outcomes were change in intensity of mechanical pain sensitivity (MPS) and dynamic mechanical allodynia (DMA) pre and post LFS. MPS was assessed as the mean of the pain ratings in response to a geometric series of 8—512 mN calibrated pinpricks at factor 2 progression, and DMA as pain to gentle stroking touch . Pain ratings to pinprick stimuli were significantly reduced following LFS  numerical rating scale (NRS), recorded daily and averaged over the last 7 days of the three-month treatment phase, compared between study groups. Of the 76 patients, 60 provided all 7 daily pain intensity scores for the primary outcome in the last 7 days of treatment, 64 provided at least 3 daily scores and 11  supplied none. The primary outcome was not statistically significant between treatment arms , and the EQ visual analogue scale (EQ-VAS) , both coMultiple imputation was used to impute data values for patients with missing data at 3 months, results suggested that there was no strong evidence of a difference between groups for any of the secondary outcomes and did not greatly differ from reported ITT results.2 lower within active group compared to sham   area determined by manual mapping surface was the only exploratory outcome demonstrating significant change between groups, being on average 74 cmMinimally important clinical differences were measured. The average percentage of patients achieving minimally important clinical difference in any given outcome domain was significantly higher in the active group compared to the sham group ,  vs 10 (36%)) compared to sham group (11 (37%) vs 19 (63%), p = 0.04). A total of 203 adverse events (AEs) were reported which were comparable between groups (2.7 ± 2.0 per person in active vs 2.7 ± 1.9 per person in sham); of these two were serious adverse events, viral meningitis and shingles, considered not to be related to the study intervention. Three AEs, all concerning increased pain during stimulation were judged as definitely related to the device (active n = 2), whilst 10 AEs were evaluated as probably related .During the Optional treatment extension/swap period NRS dropped by 1.0 points for those who extended active treatment . Those who switched from active to sham experienced a worsening of pain by 1.5 points . There were no significant outcome changes for the other two subgroups following this extension period.Post-hoc analysis using baseline disease characteristics, demographic information and outcome responses provided no evidence of a meaningful relationship between outcomes and variables. Post-hoc analysis using QST information in relation to responder and non-responder profiles additionally did not yield any meaningful outcome, on the background of small numbers and dilution from sham allocation in the trial.Post hoc telephone interview was conducted to understanding patients experience of treatment. All patients who observed the stimulation as painful (n = 6/12) reported analgesic effect, but those who observed the treatment as either ‘uncomfortable’ or ‘not painful’ (n = 6/12) experienced no analgesic benefit. Patients indicated that the timing of their stimulator use was not influenced by their pain experiences, but more frequently conducted at a set daytime, Fig. We performed a combined RCT and mechanistic study to assess the effect of LFS via peripheral nerve stimulation treatment in patients with neuropathic pain after nerve injury. Mechanistic study results demonstrate consistent evidence for the induction of pain-LTD, and a corresponding significant reduction in stimulus-evoked pains in the affected areas, i.e., reduced hyperalgesia, which was further supported by the RCT outcomes.External non-invasive low frequency peripheral nerve stimulation did not significantly reduce patients’ spontaneous pain, the primary RCT outcome. A trend toward a positive outcome across all outcomes in response to the active treatment rather than a definite effect supported by statistical change was observed. The intervention was well tolerated.As mechanisms between neuropathic pains differ, we assessed QST profiles for all patients entering the mechanistic study at baseline and the results confirm that we had recruited the targeted group of patients who displayed a mechanical hyperalgesia sensory profile Fig. ; this prThe underpinning mechanism for pain-LTD is an intermediate rise of postsynaptic calcium concentration in nociceptive dorsal horn neurons (> 1 µM/L) inducing long-lasting depotentiation of synaptic transmission via increased phosphatase activity, diminishing postsynaptic LTP maintenance mechanisms. Under conditions of LTD only a small volume of calcium permeates into the post synaptic cell, which reduces the availability of receptors by translocation and consequently weakens synaptic efficacy . The priUnlike in preliminary open-labelled studies using the same stimulator device , 14, redIt is, however, also possible that reduction in stimulus-evoked pain in some patients does not fully translate into reduction of their spontaneous pain. Although we were recently able to show in a genotype–phenotype association study that more punctate hyperalgesia predicted stronger ongoing pain the correlation still remained low . A discoPain is a subjective experience and therefore how it is evaluated will depend on contextual factors such as emotional wellbeing, physical functioning, and social occupational factors , 28, 31.The current work was informed by clear mechanistic objectives and presents a novel approach of combining clinical and mechanistic study designs to evaluate and validate therapeutic potential. The RCT included successful recruitment and retention of a very specific group of patients with neuropathic pain, verified by QST, in consenting patients, which also validates the clinical recruitment criteria used. Patient selection could have been further strengthened by the inclusion of neuropathic pain specific screening questionnaires. The development and use of a true sham intervention with some perceivable but in-efficient stimulation parameters is a further strength—the lack of credible sham intervention has previously been noted as a limitation in neuromodulation trials , 42. TheA limitation of the mechanistic study was the exclusion of a measure of spontaneous pain. Spontaneous post-test pain has a strong subjective component whilst other QST measures provide more objective assessments of pain processing. Given the subjective nature of this measure and the lengthy testing protocol (4 h) within the mechanistic study, we considered this measure would be too confounded to provide useful data. Ways of overcoming this should be considered in future study designs. Reduction in spontaneous pain intensity was not observed in the RCT and therefore LFS may not reduce spontaneous pain. We also recognise that suboptimal stimulation in the RCT may have influenced outcomes. The RCT protocol allowed patients to continue treatment without further advice or corrections after initial training. Post-hoc interviews have highlighted that this approach might have diminished the intervention’s effectiveness. Furthermore, within the RCT patients stimulated just outside the area of pain whilst in the mechanistic study stimulation was performed within the area of pain. Stimulation outside the area of the parent axon would have required deeper depth of penetration to drive axonal transmission along the nerve to the area of pain. Evaluation of stimulator use was limited as devices were not equipped with a system to monitor compliance or settings. Additionally, stimulation parameters were not recorded as part of the study. In normal practice, suboptimal stimulation may be improved with education relating to stimulation electrode positioning and coverage, but due to blinding this was not possible in the RCT.A further limitation to the RCT is the inclusion of patients who may not have benefited from treatment such as patients on high dose opioids, psychological co-morbidities or potentially unresponsive to single nerve stimulation pain conditions which could have inadvertently underpowered the study. For example, we included patients with postherpetic neuralgia , radiotherapy induced nerve pain  and medication induced nerve pain . PHN is typically associated with multisegmented dorsal horn atrophy which in turn limits the ability to correctly target a singular peripheral nerve with stimulation. Whilst radiotherapy and medication induced nerve pain is rarely confined to the distribution of one nerve. The three patients included with the later indications all experienced hand pain and only reported pain in the radial or ulnar nerve territory following said treatments; of note none of these patients had participated in the mechanistic study.before delivery of any effective stimulation and therefore we cannot confidently exclude any unaccounted-for unblinding effect and its impact on outcome.A further RCT limitation was incomplete availability of QST data for all patients included in the RCT. Broad availability of QST information might aid better understanding of responder and non-responder profiles supporting the stratification of patients in future studies. Patients were asked to indicate if they felt they had been assigned to a more or less effective intervention. Within the active group, most patients correctly identified that they had received the more effective treatment which may reflect that more patients experienced treatment benefit. A formal assessment of blinding however was not included during initial training, i.e., Neuropathic pain can persist long after the initial cause has resolved and is often severely debilitating , affecti


Background: Although pain is common in amyotrophic lateral sclerosis (ALS) and an effectively treatable symptom, it is widely under-recognized and undertreated. This study investigates epidemiological and clinical characteristics of pain, its impact and pharmacological treatment in ALS patients. In addition, opportunities for further optimization of pain therapy need to be identified. Methods: Patients from three German ALS outpatient clinics were asked to complete the Brief Pain Inventory and the ALS Functional Rating Scale—Extension and to participate in semi-structured telephone interviews. Results: Of the 150 study participants, 84 patients reported pain. Pain occurred across all disease stages, predominantly in the neck, back and lower extremities. It was described with a broad spectrum of pain descriptors and mostly interfered with activity-related functions. Of the 84 pain patients, 53.8% reported an average pain intensity ≥4 on the numerical rating scale (NRS), indicating pain of at least moderate intensity, and 64.3% used pain medication. Irrespective of the medication type, 20.4% of them had no sufficient pain relief. Thirteen out of 30 patients without pain medication reported an average NRS value ≥4. Eleven of them—mainly in the context of high pain interference with daily functions—were supposed to benefit from adequate pain therapy. However, many patients had relevant concerns and misconceptions about pain therapy. Conclusion: Given the frequency, extent and multi-faceted impact of pain, it is necessary to systematically assess pain throughout the disease course. Potentials to optimize pain therapy were seen in the subset of patients with insufficient pain relief despite medication and in those patients without pain medication but high pain interference. However, there is a need to respond to patients’ barriers to pain therapy. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with rapidly progressive muscle wasting and paralysis. Most patients die within 3 to 5 years of onset due to respiratory complications and ventilatory failure .Symptomatic treatment is the cornerstone of current clinical care and is centered on alleviating symptoms and enhancing patients’ remaining quality of life . A recenStudies focusing on pain in ALS report considerably variable prevalence, ranging from 40% to 85% ,7,8. TheThere is consensus from population-based controlled studies that patients with ALS suffer more frequently from pain ,6,12, haGiven the fact that pain is a frequent and bothering symptom in patients with ALS, it offers a clinically relevant target in optimizing symptom management.However, in contrast to the clinical relevance of pain, there is no robust information on the effectiveness of the various treatments that are currently in clinical use for the management of pain in ALS ,14. PatiThere is ample evidence in the literature that a considerable proportion of ALS patients reporting pain do not receive any pain medication. This proportion ranges from 13% to 53% of the patients with pain between studies ,12,15,16Therefore, a study of a large cohort of ALS patients is needed to critically appraise ALS-related pain therapy and to characterize those patients who suffer from pain and do not receive any pain medication. This may help to identify patients with potential benefit from pain therapy. Further research is warranted to explore ALS patients’ concerns towards analgesic medication. This knowledge will help to overcome barriers leading to unrelieved symptom distress and may thus contribute to improving patient-centered pain management strategies.This prospective multi-center study aimed to examine epidemiological and clinical characteristics of pain as well as its impact on daily living in patients with ALS. It further evaluated the pharmacological pain therapy and pain relief through certain drug classes and combinations on an individual patient basis. Patients with pain who did not receive any pain medication were further evaluated and characterized to identify patients who may benefit from pain therapy.This study was approved by the institutional ethics committee of the University of Magdeburg and was conducted between June 2015 and June 2019. Patients with ALS were consecutively recruited during clinical consultation through the outpatient clinic at the University of Magdeburg. Further patients were asked to participate in this study at the outpatient clinics of Hannover Medical School and Charité Universitätsmedizin Berlin. They were subsequently contacted by a project team at the University of Magdeburg.Exclusion criteria were insufficient comprehension of the German language or severe cognitive impairment, evaluated by clinical judgement during medical consultation, rendering adequate answering of the survey impossible.A total of 182 patients were recruited for this study and provided written informed consent before enrollment.All patients were diagnosed according to the revised El Escorial criteria . The patAll phone calls were conducted after making an appointment with the patient. During the contact, we collected demographic and clinical information such as disease duration and supportive therapy, e.g., placement of a percutaneous gastrostomy tube and implementation of non-invasive ventilation (NIV). Further questions were asked about pain and pain medication or possible barriers to using it. In addition, the patients were asked whether they suffered from muscle cramps. In case of specific pain problems, such as pain in the face, deeper questions were asked to find out more about the cause, e.g., mask-induced skin lesions or pressure ulcers. Therefore, the use, type of NIV interface and the tolerance of NIV were elicited.For patients who were unable to conduct the interview due to pronounced bulbar symptoms or dyspnea, it was possible to conduct the interview with the help of a relative. During the phone calls, detailed notes of the responses to the questions were taken and analyzed descriptively.Subsequently, questionnaires were sent home to the patients. To assess physical functioning, patients were asked to complete the disease-specific ALS Functional Rating Scale—Extension (ALSFRS-EX), which consists of 15 items in four subscales  and has been validated as a patient-reported measurement instrument in the German language ,22. The To categorize the different levels of pain intensity of the BPI, we used cut-point 3 for mild–moderate and cut-point 6 for moderate–severe pain referring to the average pain intensity scale . The BPIIn accordance with previous literature, pain interference scores ≥7 were categorized as high .Pain relief of at least 10% is regarded as minimal, values ≥30% are considered as a moderate degree of pain relief and values ≥50% are considered as substantial improvements due to pain medication .The assessment instruments were completed by the patients or, if this was not possible, by their relatives or caregivers according to the patient’s information, and then returned.Patients with pain who did not receive any pain medication were stratified according to their pain-related features. First, they were classified into patients with mild and at least moderate pain  referring to the average pain intensity scale. In the next step, we analyzed whether those patients with at least moderate pain intensity differed in their ALS-related clinical characteristics from those receiving pain medication, and whether patient-reported barriers to pharmacotherapeutic pain management were present in these patients. They were further characterized to identify patients with high pain interference with daily functions who may benefit from pain therapy.Statistics were calculated with IBM SPSS, Version 24 . For demographic and clinical data, descriptive statistics  were performed.t-test or the Mann–Whitney U test for continuous data depending on the distribution of the data. The significance level was set at α ≤ 0.05, unless stated otherwise, and corrected for multiple comparisons using Bonferroni adjustments, if necessary.Correlations were assessed using Pearson’s and Spearman’s tests for normally and non-normally distributed data, respectively. For the interpretation of effect sizes, correlation values between 0.10 and 0.29 were considered weak, from 0.30 to 0.49 moderate and from 0.50 to 1.00 strong . CompariA detailed flow diagram of the recruitment including drop-outs is provided in p = 0.037) than patients without pain and had a significantly lower ALSFRS-EX sum score (p = 0.003), indicating more physical impairment with significantly lower gross motor (p = 0.012) and fine motor (p = 0.003) subscores. Regarding the other demographical and clinical data, no significant differences were observed between the two groups.Datasets of 150 patients were finally included in this study. Eighty-four patients had sufficient pain to fulfill the criteria of the BPI to complete the entire questionnaire. Accordingly, pain was prevalent in 56% of the patients. Patient-referred data of the patients with and without pain are reported in Of the 84 pain patients, the majority (84.3%) attributed their pain to ALS, and approximately one quarter (27.4%) had experienced pain at the time when ALS was diagnosed.The pain intensity ratings for the average and most severe pain in the past week are presented in Pain locations are visualized on front and back body diagrams in Eight out of 26 patients (30.8%) with pain requiring NIV reported painful skin lesions over the nasal bridge due to the NIV mask, which corresponds to 9.5% of the 84 patients with pain. In six patients, these lesions were specified as pressure ulcers. Seven out of these eight patients used orofacial masks and one patient used a nasal mask. The extent of NIV use was 20 per 24 h in one patient, 10 h in two patients and 7 h in two further patients. Three patients reported that they had difficulty tolerating NIV, using it only intermittently and for a variable number of hours a day.The patients’ ratings for the different pain qualities are depicted in When focusing on items representing the affective component of pain perception, most of the patients (82.9%) described their pain as “exhausting, tiring”, followed by “unbearable” (57.8%) and “miserable” (57.1%). Of the nociceptive pain descriptors, “cramping/colicky” ranks first (70%) and “dull, pressing” second (57.4%). The item “throbbing” was clearly less frequently chosen for pain description (21.9%). Among the neuropathic pain descriptors, “drawing, tearing” (69%), “shooting” (42.9%) and “stabbing, gnawing” (51.5%) were mentioned most frequently. The neuropathic pain qualities “burning” (31.3%) and “pain with light touch” (29.2%) were regarded as less appropriate for pain description. Patients selected on average 4.7 ± 2.6 terms to describe their pain.In addition to the pain qualities in the BPI, patients were asked during the telephone interviews whether they suffered from muscle cramps in order to specify the item “cramping/colicky” of the BPI. This was confirmed by 69% of the patients.The pain-related pharmacotherapy is presented in Of the 84 pain patients, 54 patients (64.3%) received pain medication. Non-opioid analgesics were most commonly used (53.6%), mainly non-steroidal anti-inflammatory drugs (NSAIDs) and metamizole. Opioids were the second most frequently used drug class (19%), with low-potency opioids being slightly more often used than high-potency opioids. A smaller proportion of the patients received coanalgesics such as anticonvulsants (12%) or antidepressants (6%). A further 13 patients received antidepressants with analgesic properties for other indications than pain relief . Seventeen patients (20.2%) received treatment for cramps, in approximately equal parts magnesium and quinine sulfate. ALS-related spasticity was treated in seven of the pain patients (8.3%), mainly with baclofen.In terms of clinically relevant degrees of pain relief, 12 patients (22.2%) had moderate and 27 patients (50%) substantial pain relief. Eleven patients (20.4%) had no sufficient pain relief (defined as pain relief <30%). With regard to the type of medication in use, the proportion of patients with no sufficient pain relief was 33.4% for coanalgesics, 18.8% for non-opioid analgesics, 20% for low-potency opioids and 16.7% for high-potency opioids.Of the 84 pain patients, 34 patients (40.5%) stated that pain medication provided pain relief. Other frequently reported non-pharmacological pain relieving factors were resting (46.4%) as well as physiotherapy and movement (36.9%). In 23 of the patients (27.4%), warm compresses improved pain.Of the 84 patients with pain, 30 patients (35.7%) did not receive any pain medication and were further stratified based upon their ratings of pain intensity and pain-related impairment. First, patients were grouped into those with mild pain (defined as NRS < 4) and those with moderate to severe pain intensity (defined as NRS ≥ 4) referring to the average pain intensity scale. Accordingly, 17 patients (56.7%) had mild pain and 13 patients (43.3%) at least moderate pain.p = 0.001). This was accompanied by a markedly lower physical impairment reflected in a significantly higher ALSFRS-EX sum score (p = 0.048) and gross motor subscore (p = 0.006).Demographic and clinical data of the 13 patients reporting an NRS value ≥4 were compared to pain patients with pain medication . A strikThe 13 patients without pain medication and an NRS value ≥ 4 were characterized with regard to their demographic, clinical and pain-related data on an individual basis see  in orderWhen asking the patients about the reasons why they did not take any pain medication, 8 out of these 11 in whom pain therapy should be considered described concerns about pain medication and provided explanations about why they were reluctant or unwilling to take pain medication see . The mosThis multi-center study in a well-characterized cohort of 150 patients with ALS showed that pain was prevalent in 56% of patients and can occur at any stage of the disease. Eighty-five percent of the patients attributed their pain directly to ALS. Pain was most frequently prevalent in the lumbar region, neck, shoulder region, buttocks and legs. The pain descriptor profile included a variety of affective and sensory pain descriptor terms. A substantial subset of the patients with pain (53.8%) suffered from an average NRS pain intensity score ≥4. Pain had a negative impact on different aspects of daily living, mostly on activity-related functions. Of the 84 pain patients, about two-thirds received pain medication, most commonly non-opioid analgesics (53.6%), followed by opioids (19%) and coanalgesics (18%). Half of the patients reported substantial and 22.2% moderate pain relief, whereas 20.4% of the patients had no sufficient pain relief. Of the 30 pain patients without pain medication, 13 reported an NRS score ≥4 for their average pain. They had a significantly shorter time since diagnosis and a better physical status than those with pain medication. We suspect that 11 of these 13 patients, mostly with high pain interference with daily functions, may benefit from adequate pain therapy. When asked about the reasons why they did not take any pain medication, many of those patients described concerns about pain therapy, mainly misconceptions about analgesics.The finding that the majority of our pain patients attributed their pain to ALS seems to be surprising because pain is a non-motor symptom and not primarily associated with ALS. However, our observation is consistent with previously published data  and emphOur study demonstrates that pain is present at any stage of the disease, which is in agreement with a previous study that pointed to pain as a common symptom in ALS regardless of the disease stage . Our stuThe pain locations most frequently mentioned in our study cohort are similar to previous findings ,7,10,11 Up to one third of our pain patients requiring NIV had painful skin lesions on the nasal bridge, including pressure ulcerations due to NIV, with half of them being poorly adapted to NIV. Indeed, this painful complication is a common reason for poor adaptation or non-invasive ventilation failure  and shouThe pain descriptor profile of our patients included multiple affective and sensory pain descriptors and reached an average number of almost five descriptor terms per patient. Previous studies congruently observed the use of a variety of pain descriptor terms in patients with ALS ,36, indiClinical studies often categorize the patients’ ratings of their pain into mild, moderate and severe pain. According to a literature review, there is a wide range of cut-points for these categories on the numeric rating scale depending on the disease and mechanism of pain . The optThe average pain intensity in our study cohort can be considered moderate and is comparable to previous studies, as was the moderate pain interference total score of the BPI as a measure for the average degree to which pain interferes with daily functions ,10. PainEven though quality of life is undoubtedly a different construct than what is measured by pain interference according to the BPI, there is a certain analogy in the predominant impact of pain on physical aspects of the respective construct. A recent study in ALS patients demonstrated that pain influences physical quality of life more than psychological quality of life .In our study, the high proportion of patients taking non-opioid analgesics is comparable with previous literature ,15, as wWhen comparing the proportion of patients stating pain medication to be a pain-relieving factor, the percentage of patients in our study was higher than in previous literature ; howeverMost studies on pain in ALS that evaluated pharmacotherapeutic management in their patients did not provide any data on those pain patients who did not receive pain therapy, although these patients presented a relevant subgroup of the respective pain patient cohorts ,10,12,16In the present study, we further characterized the patients with pain who did not receive any pain medication and stratified them based upon their ratings of pain intensity and pain interference to identify those patients who may benefit from pain therapy. Generally, chronic pain patients with mild pain can be expected to have their pain adequately controlled, while patients with moderate or severe pain need a treatment reevaluation . HoweverWe suspect that 11 of these 13 patients, who mostly experienced high pain interference with daily functions, may profit from appropriate pain management. However, we found relevant patient-reported barriers to pain therapy in many of them. We assume that these barriers may have essentially contributed to the underreporting of pain in many of these patients or prevented them from wanting to mention their pain during consultations with their doctors.Our study showed that the barriers to pain therapy were mainly misconceptions about analgesics. Careful exploration of these barriers offers the treating physician an opportunity to appropriately address these concerns within a patient-centered interaction to help to overcome barriers contributing to unrelieved symptom distress and to propose viable options for the respective patient to relieve pain-related suffering.Although this study focused on pharmacotherapeutic pain management, the management of pain should involve a multiprofessional approach and consider suitable non-pharmacological treatment options, which may be valuable and successful in the management of chronic pain . A closeFurther research on pharmacological and non-pharmacological treatments in different types of ALS-associated pain conditions is warranted to support clinical decision-making and to improve the management of pain in patients with ALS.A potential limitation of this study is that the categorizations of the different levels of pain intensity and of pain interference with daily functioning were derived from studies on chronic pain and have not been verified in patients with ALS. Moreover, the patients’ tolerability of pain and preferences for treatment as relevant factors involved in analgesic decision-making were not accounted for in our study. Lastly, our data refer to patients who, in their vast majority, regularly attended medical consultations in specialized ALS outpatient clinics, which may limit the generalizability of our findings.Given the frequency, the extent and the multi-faceted impact of pain on daily living in ALS patients, it is necessary to systematically assess pain throughout the course of the disease to meet the needs of ALS patients with pain. Effective treatment of pain has the potential to improve the remaining quality of life, which is of utmost importance when survival time is so limited. This study identified opportunities to optimize pain therapy in a subset of patients with insufficient medication-related pain relief and in an equally large proportion of pain patients without pain medication who mostly experienced severe pain interference with daily functions. In the latter, we found relevant patient-reported barriers to pain therapy, which should be carefully evaluated and addressed appropriately. This can help to overcome barriers contributing to unrelieved symptom distress and may thus contribute to improving pain management strategies in individual patients with ALS.


Cissus quadrangularis Linn. (CQ) is a medicinal plant with good evidence for the treatment of hemorrhoids, listed in the Thai National List of Herbal Products in the oral dosage form. Acmella paniculata  R. K. Jansen. (AP) is a medicinal plant with a local anesthetic effect.  To investigate the potential of rectal suppositories containing CQ and AP extracts to alleviate symptoms of hemorrhoids compared with the commercialized rectal suppository containing hydrocortisone and cinchocaine. n = 105) with different severity grades  from eight hospitals in northern Thailand were included in this study. Hemorrhoid severity was graded by proctoscopy associated with either anal pain or bleeding related to hemorrhoids or both. The patients were randomly allocated to two groups: CQ-AP group (n = 52) or the commercialized rectal suppository group (n = 53). One suppository was rectally administered twice daily in the morning and at bedtime for seven days. Evaluations were performed by physicians on days 1, 4, and 8 of the study. The primary endpoints were bleeding and prolapse size, while the secondary endpoint was anal pain.  Hemorrhoid outpatients ( Baseline demographics, lifestyle, constipation, number of prolapses, grade of hemorrhoid severity, and duration of experiencing hemorrhoids were comparable in both groups of patients. The effects of CQ-AP and the commercialized rectal suppository on bleeding, prolapse size, and anal pain were comparable. The patients in both groups were satisfied with both products at comparable levels and stated a preference for further use in the case of hemorrhoids recurrence. In terms of safety, the patients in the commercialized rectal suppository group experienced a higher incidence of adverse events, including anal pain and bleeding.  Rectal suppositories containing a combined extract of CQ and AP show potential in alleviating hemorrhoidal symptoms with a good safety profile. Cissus quadrangularis Linn. (CQ) has long been used for hemorrhoids because of its vasoconstrictive effect and anti-inflammatory activity [Acmella paniculata  R. K. Jansen (AP)  is a herb distributed throughout South Asia to Indochina Peninsula including Thailand and known to have a local anesthetic and anti-inflammatory activities; however, its toxicity has not yet been announced, and reports on the toxicity of this genus are very limited [Hemorrhoid is an anorectal disease caused by venous dilatation in the rectum and anus. Clinical manifestations of hemorrhoids commonly found in the early phase include bleeding during or after defecation. Pain, itching, and/or prolapse in the anus can sometimes be found . The preactivity , 5. In aactivity . Regardiactivity , 8. Theractivity . Acmella limited . Althoug limited , 12, then = 4), Lamphun (n = 1), Phayao (n = 1), Chiang Rai (n = 1), and Phitsanulok (n = 1) provinces, from May to June 2018. This study was conducted in accordance with good clinical practice and was approved by the Ethical Committee of the Faculty of Pharmacy, Chiang Mai University (study number 34/2017). The study project was funded by the Department of Thai Traditional and Alternative Medicine, Ministry of Public Health, and registered in the Thai Clinical Trials Registry (study ID: TCTR 20180501002).This study was a multicenter, randomized, double-blind trial conducted in eight hospitals located in northern Thailand, namely, those in the Chiang Mai , pregnancy, breast feeding, menstrual period, history of anorectal surgery in the past year, malignancy, inflammatory bowel disease, immunocompromised status, anticoagulant use, and medication for hemorrhoids within 7 days prior to the initiation of the study. The discontinuation criteria were as follows: serious bleeding or serious adverse events considered unsafe by a physician, need to take corticosteroid in the oral or topical or injection form, missed follow-up at visit 2 or 3, and withdrawal from the study.CQ-AP suppositories containing CQ extract (1.0% w/w) and AP extract (10.0% w/w) were prepared in the Thai Traditional Medicine Laboratory of the Faculty of Pharmacy, Chiang Mai University, which has been certified for Good Manufacturing Practice. The resulting suppositories were administered to the CQ-AP group, while the commercialized rectal suppository containing hydrocortisone (5 mg) and cinchocaine (5 mg) was administered to the corresponding group.n = 53) or the commercialized rectal suppository ® (n = 57). The patients were informed to take one suppository twice daily, in the morning, and at bedtime for 7 days. If defecation occurred within 30 minutes of application, another suppository would be reinserted. The patients in both groups were advised to consume a high-fiber diet and drink plenty of water without taking any laxatives. The patients were contacted via phone or home-visited by a nurse or practitioner of Thai traditional medicine on day 2, day 3, and day 7 to maximize adherence, monitor adverse drug events, and inform them of their next visit.Patients were randomly assigned to receive either a CQ-AP  primary outcome: bleeding severity  and prolapse size; (2) secondary outcome: anal pain using the visual analog scale (VAS) from 0 to 10.n = 110) were randomly allocated to two groups, CQ-AP and the commercialized rectal suppository, by a pharmacist in the participating hospitals, using a block randomization method with a block size of 4. The physicians, researchers, and statisticians were blinded to patient allocation. The patients were not informed about the type of suppository they received.Eligible patients  for bleeding severity and anal pain in each group compared to baseline. When significance was found between each of the visits, the Bonferroni post hoc test was used for analysis. The analysis was subjected to intention-to-treat analysis, and the missing values were replaced using the last observation carried forward method. A n = 112) were screened for eligibility between May 2018 and June 2018, of whom seven were excluded. Two out of seven patients did not meet the inclusion criteria, whereas the reasons for excluding other patients were co-occurrence of the menstrual period (1), incomplete baseline data (1), request to withdraw (1), and missed follow-up (2). A total of 105 patients  completed the study.This study revealed the potential effects of a rectal suppository containing CQ in combination with AP extracts. The therapeutic effects were found to be comparable to those of the commercialized rectal suppository, which contains hydrocortisone and cinchocaine, on hemorrhoids in a double-blind randomized controlled trial. This study was a multicenter study carried out in eight provinces in the northern part of Thailand, which contributes to the generalizability of the results.®, which contains bioflavonoid hesperidin and an extract of Ruscus aculeatus, reduced bleeding, pain, and prolapse to a similar extent. Additionally, Kanket et al. demonstrated a comparable effect between orally administered CQ and flavonoids on bleeding, pain, and prolapse [Although there are reports regarding the efficacy of CQ in the treatment of hemorrhoids , 12, theprolapse . Anotherprolapse .This study is the first to evaluate the efficacy of CQ extract in combination with AP extract as a rectal suppository, which is more likely to be well-tolerated compared to the oral dosage form. The efficacy of the CQ-AP and the commercialized rectal suppository for anal pain, bleeding, and prolapse on days 1, 4, and 8 were comparable. Bleeding, which was the primary outcome, was markedly improved in both groups. The size of the prolapses was markedly reduced by both treatments. The CQ-AP suppository provided comparable anal pain relief to the commercialized rectal suppository, although earlier onset of pain relief was observed in the commercialized rectal suppository group. The efficacy of CQ on anal pain, bleeding, and prolapse was in agreement with the findings of Panpimanmas and Lekutai , 12.The effect of CQ on anal pain may be due to its anti-inflammatory activity , 5 and aIn terms of tolerability, a few patients in the CQ-AP group experienced adverse events, including anal pain, bleeding, and anxiety. However, in the commercialized rectal suppository group, a greater number of patients experienced adverse events, namely, anal pain, bleeding, and mucus leakage from the anus. Some adverse events, such as anal pain and bleeding, were minor in severity and may not be related to the treatment, rather the signs and symptoms of hemorrhoids.In addition to objective parameters, subjective parameters, such as patient satisfaction with both medications, were also assessed in this study. All recruited patients showed a high satisfaction with both treatments, and the mean satisfaction score of the CQ-AP suppository was insignificantly greater than that of the commercialized rectal suppository. Both groups were willing to use their corresponding treatments as needed.The limitation of this study was the pilot design with no sample size calculation. Further studies should include a larger number of patients to obtain more information regarding efficacy and safety.In conclusion, this pilot study demonstrated promising results regarding the potential efficacy of the combined extract of CQ and AP in rectal suppositories for hemorrhoidal treatment, with a good safety profile, as an alternative to conventional treatment, such as the commercialized rectal suppository and other suppositories containing similar active ingredients.


There is limited evidence concerning radiotherapy for painful lymph node metastases (PLM). We evaluated the effectiveness of radiotherapy for PLM using the International Consensus Endpoint in a subgroup analysis of a prospective observational study.In the primary study, 302 patients received radiotherapy for painful tumors. Among them, those treated with palliative radiotherapy for PLM were analyzed in the present study. We used the Brief Pain Inventory short form to evaluate the intensity of pain and the pain interference in patient's life. We collected the Brief Pain Inventory and analgesic data at baseline and at 1, 2, and 3 months after the start of radiotherapy. Pain response was assessed using the International Consensus Endpoint. Patients were diagnosed with a predominance of other pain (POP) if non-index pain of a malignant or unknown origin was present and had a greater 'worst pain' score than the index pain.Radiotherapy for PLM was performed on 25 patients. In total, 15 (60%) patients experienced a pain response. The pain response rates for evaluable patients were 66%, 67%, and 57% at 1-, 2-, and 3-month follow-ups, respectively. At baseline and at 1, 2, and 3 months, the median index pain scores were 7, 2, 0, and 0.5, respectively. At 1 month, all pain interference scores were significantly reduced from baseline. Four (16%) patients experienced POP within three months.Radiotherapy for PLM improved pain intensity and pain interference. Palliative radiotherapy may be a viable treatment option for PLM. Radiotherapy is an important treatment option for cancer-related pain , 2. The To the best of our knowledge, few small studies have investigated radiotherapy for painful lymph node metastases (PLM) , 11; howIn a subgroup analysis of a prospective observational study, we evaluated the effectiveness of radiotherapy for PLM using the International Consensus Endpoint in 2012 [We performed a subgroup analysis of a previously published prospective three-center observational study. In the primary study, 302 patients were scheduled to receive radiotherapy for their painful tumors. We sought to identify the predictors of pain response after radiotherapy for painful tumors . Among tThe patients were evaluated as previously reported . The BriWe collected the BPI and analgesic data at baseline and at 1, 2, and 3 months after the start of radiotherapy. Pain response was assessed using the International Consensus Endpoint for clinical trials in bone metastases . PatientNon-index pain was assessed in addition to the index pain. The treating radiation oncologists differentiated between index pain caused by the irradiated tumor and non-index pain, the cause of which was not treated with radiotherapy . At baseP values less than 0.016 were considered significant. Bonferroni correction was applied for multiplicity. Overall survival, calculated from the initiation of radiotherapy, was estimated using the Kaplan–Meier method. Statistical analyses were performed using R version 4.0.2.The Wilcoxon signed-rank test was used to compare two-time points . Two-tailed Among 302 patients analyzed in the primary study, 25 patients received radiotherapy for PLM Fig. . All patIn total, 15 (60%) of 25 patients experienced a pain response , and four (16%) of 25 patients experienced POP within three months after the start of radiotherapy Tables . The paiThe median daily OMED at baseline and at the 1, 2, and 3 months of follow up were 15, 23, 15, and 26.5 mg, respectively.The pain interference scores at baseline and at 1, 2, and 3 months of follow-up are shown in Fig. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events version 4.0. In total, eight (32%) of the 25 patients experienced grade 1 toxicity, and four (16%) experienced grade 2 toxicity within three months after the start of radiotherapy. No patient experienced grade 3 or higher toxicity. Eight patients experienced dermatitis , and two patients experienced esophagitis . Pneumonitis (grade 2), enterocolitis (grade 1), anorexia (grade 1), pharyngeal mucositis (grade 2), and dysgeusia (grade 1) were experienced by 1 patient each.The median follow-up of all patients was 7.3 months. The median overall survival was 7.3 months .To the best of our knowledge, this was the first prospective study to analyze the effectiveness of palliative radiotherapy for PLM. We found that radiotherapy was an effective treatment for pain relief, with a pain interference reduction in PLM. As early as 1 month follow-up, all seven subscales of the pain interference were significantly reduced from baseline. POP was observed in some patients only.There has been a few previous studies on palliative radiotherapy for PLM, with which we could compare our findings. A retrospective study that examined 68 patients receiving radiotherapy for retroperitoneal lymph node metastases reported 20 patients who presented with pain. Among them, 14 patients had extra-retroperitoneal metastases, and the other six patients had isolated retroperitoneal lymph node metastases . On a 0–A systematic review of radiotherapy for painful bone metastases in prospective nonrandomized studies reported a pain response rate of 55% and a complete response rate of 15% . These rWe previously showed that in patients with POP after radiotherapy, opioid analgesic use increased, potentially lowering the response rates . In the This study had certain limitations. First, a small number of patients were assessed in this study. The sample size hampered the analysis of the predictors of pain response. Future larger studies are necessary to analyze the relation between pain response and patient/tumor/treatment characteristics, preferably by multivariable analysis. Second, the present study was post hoc, and our subgroup analysis was not a priori declared. The study findings should be confirmed in future studies. Third, the rates of attrition were relatively high, which is expected in studies investigating palliative radiotherapy .In the present secondary analysis of a prospective observational study, radiotherapy for PLM improved pain intensity and pain interference with mild toxicity. Palliative radiotherapy may be a viable treatment option for PLM. Larger studies are warranted to investigate the efficacy and toxicity of palliative radiotherapy for PLM.


These results were consistent with those of a previous study showing that high-level cognitive deficits were prominent in NF1 patients when performing challenging tasks. The mechanisms and related brain network activity underlying these deficits should receive attention in the future.Cognitive impairments and social-function deficits are severe complaints in neurofibromatosis type 1 (NF1) patients. Empathetic pain perception may be disrupted in NF1 patients because of high-level cognitive deficits. This study investigated the empathy profiles of adult patients with NF1, especially concerning whether explicit and implicit empathetic pain perception are abnormal in this population. We examined empathetic pain perception through a paradigm based on perceiving another person’s pain; in this task, patients were required to make judgments about the presence of pain or the laterality of the body part, as shown in a picture. Twenty NF1 patients without obvious social or communication difficulties completed the task, and the results were compared with results from the normal controls (NCs). Regarding explicit empathetic pain processing, i.e., judging the presence of “pain” or “no pain”, there were no significant differences between patients and controls in accuracy or reaction time. However, in implicit empathetic processing, i.e., judging the laterality of “pain” or “no-pain” pictures, NF1 patients had significantly lower accuracy ( Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disorder with an incidence of approximately 1 in every 2700–3000 live births ,5,6.Empathy is critical for effective social interactions, and any impairment in empathetic pain perception is a notable deficit in persons with diseases such as ASD and in those with focal brain lesions ,8. EmpatIn this study, we recruited 20 NF1 adult patients with no complaints of social interaction problems and 20 matched normal controls (NCs) to assess and compare empathetic pain perception using the “empathy for others’ pain” (EOP) task ,8,9. We Twenty-six NF1 adult patients were recruited through neurology and neurosurgical clinics involved in the study. All participants with NF1 had fulfilled the diagnostic criteria specified by the National Institute of Health Consensus Conference . Four paAll participants were right-handed, without previous or current diagnosis of autism, ADHD, or related behavioral problems. The same experimental procedures were performed in all participants. Individual written consent was obtained from all participants, and the study was approved by the Institutional Review Board of the Beijing Tiantan Hospital, Capital Medical University (KY 2019-027-02).Pre-task evaluations were previously described in . All parExperimental stimuli and procedures were the same as those described in previous studies ,8. Briefp < 0.05 was considered significant between the patient and control groups.Accuracy and RT were analyzed for the four different conditions  in the EOP task. The participants’ sensitivity to pain and laterality was measured by the discrimination index d’, and decision bias was measured by the index β using signal detection theory (SDT) . In the The gender, age, education, BDI score, and MMSE characteristics are shown in p = 0.095) (p = 0.16) and gender (p = 0.74). The NF1 patients had an approximately two-year shorter education duration, but the difference was not significant.All patients were free from cognitive impairment, as measured by the MMSE, and had slightly higher baseline BDI mood scores (indicating lower mood status) than the controls; the difference was close to significant (= 0.095) . Most ofFor explicit empathetic pain processing under TP conditions, there were no significant differences between the patients and controls in d′ and β during pain judgment (results shown in p = 0.038), as compared to the NCs, and a significant increase in the mean pain RT (p = 0.004). No significant difference was shown in β during pain judgment and cost of pain RT . The NF1 patients showed significant differences in d’ scores , the NF1 patients showed difficulties and deficits, suggesting dysfunction in the patients’ high-level processing networks. Few studies have focused on empathetic perception in NF1 patients. Experimental studies employing a similar strategy have been performed in NF1 patients. In a previous study, the Awareness of Social Inference Test (TASIT) was administered to adult NF1 patients and normal controls. In that study, the patients performed normally when recognizing direct sarcasm but were impaired in their ability to understand paradoxical sarcasm and sincerity. In addition, patients also had significant deficits in the recognition of facial expressions of emotion, especially anger . NF1 patThe mechanisms underlying this dissociation have been under debate, and we have highlighted three possible explanations. First, the differential responses under direct and indirect stimuli could be explained by the structural hypothesis that direct stimuli evoke the mirror neuron system, whereas indirect stimuli such as “facial emotion” are involved by an alternative process . AccordiCognitive and social difficulties in NF1 patients have drawn increasing attention in recent decades. When measured by IQ, general intelligence is slightly lower is these patients than in normative comparison groups, but it is usually only mildly affected. Similarly, the difference in general cognitive function measured by the MMSE between the NF1 patients and NCs was not significant in our study. The NF1 patients had a shorter education duration (10 years versus 12 years) than the NCs, but the difference was not significant. However, van der Vaart confirmed that a broad range of cognitive deficits and behavioral problems were detected in patients with NF1 across clinical trials . AcademiSeveral studies have discussed the social difficulties of NF1 patients, mostly based on subjective scoring and questionnaires answered by others about the patients, providing multiple perspectives in various contexts. Scores from parents and teachers rated children with NF1 with lower scores on the social skills rating system (SSRS), indicating clinical social difficulties in NF1 children . RatingsDeficits in empathetic pain perception may result in social problems and communication difficulties, and more specific studies should be conducted to identify these problems in relation to NF1 patients. In our study, there was a limited assessment of ASD characteristics in our patients. In the future, such differentiation should be explicitly carried out. On the other hand, clinical trials aimed at improving cognitive deficits in NF1 patients have been reported in the literature. Methylphenidate has been shown to improve attention difficulties in trials ,28. LovaAnother research direction could be to identify the particular brain regions that contribute to emotion and social skills, such as empathy and anger. Functional MRIs should be attributive, and studies have been performed in several centers. Comparing patients and NCs could be an effective way to clarify the abnormalities and advance our understanding of brain function.In summary, the current study suggested that implicit empathetic pain perception was disrupted in NF1 patients, as compared to the NCs, though patients exhibited normal explicit empathetic pain perception. This gives rise to the concern that social and cognitive deficits in NF1 patients only become apparent when complicated and challenging tasks are performed. The mechanisms and related brain network activity underlying these processes should be given special attention in the future.


Background and Objectives: Musculoskeletal dysfunction can induce several types of chronic pain syndromes. It is of particular interest to elucidate the pathomechanism of different forms of chronic pain. It is possible that patients who have developed chronic widespread pain (CWP) may endure different pathomechanisms as compared to those who suffer from local pain  and regional pain , especially with regard to pain regulation and its related biomediators. The aim of this study was to determine the differences in pathomechanisms among these patients by measuring pain-related biomediators, particularly brain-derived neurotrophic factor (BDNF). Additionally, subpopulations of immune cells were determined in parallel. Materials and Methods: Patients and healthy subjects (HSs) were recruited (age and gender-matched). BDNF was measured from serum samples of patients and HSs and the data of body composition parameters were recorded. Additionally, both patients and HSs were asked to fill in questionnaires related to pain intensity, anxiety, and depression. Results: Our results highlight that the levels of both free and total BDNF are significantly lower in pain patients compared to HSs, with p values of 0.041 and 0.024, respectively. The number of CD3− CD56bright natural killer (NK) cells shows significant differences between the groups. Comparing all chronic pain patients with HSs reveals a significantly lower number of CD4+ CD8+ T cells (p = 0.031), CD3− CD56bright NK cells (p = 0.049) and CD20+ CD3− cells (p = 0.007). Conclusions: To conclude, it seems that a general conformity between the pathomechanisms of different chronic pain diseases exists, although there are unique findings only in specific chronic pain patients. Pain is considered chronic when it lasts for more than three to six months after the healing of the original injury or recurs repeatedly . ChronicOsteoarthritis (OA) is one of the most prevalent chronic pain disorders . The preLow back pain is defined as “pain, muscle tension or stiffness localized below the costal margin and above the inferior gluteal folds, with or without leg pain (sciatica)” . The likChronic widespread pain (CWP), such as fibromyalgia syndrome (FMS), is a disorder of pain regulation with central sensitization . CWP is Central sensitization is a form of maladaptive neuroplasticity underlying many chronic pain disorders, including neuropathic pain, fibromyalgia , some foAs afore-mentioned, chronic musculoskeletal pain patients suffer from psychological symptoms, sleep deprivation, and other mental-related issues ,27. SomeThis study was a cross sectional study and performed according to the principles of Helsinki (1961). It was approved by the Ethics Committee of Hannover Medical School (No. 6554). Setting: University hospital.Inclusion. To be included, all patients  should have a history of pain for at least three months. This study focused on three different types of chronic pain patients, with a score of a minimum of ≥4 on the Visual Analogue Scale (VAS) during the last week before the day of recruitment. Patients were 18 to 70 years of age and understood the German language. The patients had to have met the criteria of the diagnosis of OA (knee(s) or hip(s)), cLBP, or CWP. The diagnosis of OA ,36 and cExclusion. Patients were excluded in cases of having a comorbidity, such as cancer, heart failure, major depressive disorder, acute and inflammatory diseases, a recent injury, symptomatic arteriosclerosis, or diabetes. Specific exclusion criteria were radiculopathy, sciatica, and any indication of immediate surgery, autoimmune and infection joint, and acute spine disease. Pregnant and breast-feeding female patients were excluded, as well.Patients were not allowed to take any pain medication within two days before blood drawing. However, in emergency cases, they were allowed to take emergency medicine.Patients were recruited by using advertisement in the local newspaper, following telephone screenings. Additionally, patients were also recruited from outpatients of the Department of Rehabilitation Medicine and other departments of Hannover Medical School, Hannover, Germany.Most HSs were staff of Hannover Medical School, Hannover, Germany. They were examined at the Department of Rehabilitation Medicine. We recruited HSs that matched the chronic pain patient group by gender and age (±2 years). All HSs should be particularly free from chronic pain and other exclusion criteria that were applied for patients.g for 15 min. Serum samples were stored at −80 °C at the Biobank of Hannover Medical School until analyzed. Free and total BDNF were measured by using conventional sandwich ELISA in serum samples . The quantification was performed against a standard curve as provided by the manufacturer in a plate reader.BDNF. Fasting blood samples (30 mL each) from an arm vein were drawn in the morning between 7:00 and 10:00 a.m. Samples were allowed to clot before being centrifuged at 1500× g), and cells were washed three times with 2 mL of PBS/BSA (3 min at 400× g). Finally, cells were resuspended in 250 mL PBS/BSA and subjected to flow cytometry analysis on a FACSCanto II  by gating on live CD45+ singlet lymphocytes and acquiring 5 × 104 to 1 × 105 events per sample in the combined gate. Offline data analysis was performed by using FSC Express V6 software . Absolute cell counts were calculated on the basis of WBC counts obtained from the Department of Hematology at Hannover Medical School.Phenotyping of peripheral blood lymphocytes by flow cytometry. Phenotyping of lymphocytes was performed by incubating 200 µL of freshly drawn heparinized whole blood with antibodies according to the manufacturers’ recommendations in 5 mL tubes. The following antibodies were used for this study: CD3 PE-Cy7, CD4 FITC, CD8 PB, CD14 BV510, CD20 APC, CD45 APC-Cy, and CD56 PE. 7 AAD was used for live cell gating . Corresponding isotype-matched antibodies were used as controls. All antibodies were purchased from Biolegend. After 20 min incubation, 2 mL of lysis solution (Biolegend) was added to each tube. Then, 10 min later, tubes were centrifuged  . AdditioThe normality of the data was checked by using the Shapiro–Wilk test. An ANOVA or Kruskal–Wallis test (depending on the data distribution) was used to compare the significance of body composition parameters, BDNF, immune cell phenotype, and HADS (anxiety and depression) followed by a post hoc test with Bonferroni correction ).p < 0.05. Subgroup analysis was performed according to the anxiety and depression score. Explorative statistics analyses, such as the correlation of biological mediators and body composition parameters, were also performed.A Student’s t-test or Mann–Whitney U test was used to compare the free and/or total BDNF between HSs and patients depending on data distribution. The mean imputation method was used for handling missing values. Statistical analyses were performed by using SPSS version 26 . Results were considered statistically significant at The most comparable research was published by Laske et al. , who anaIn total, 670 participants were asked to participate in this study. Due to different reasons, such as exclusion criteria, time schedule, and the distance from participants’ addresses, final data from 37 patients with OA, 38 patients with cLBP, 37 patients with CWP, and 35 HSs were analyzed . None ofp = 0.001) as well as between CWP patients and cLBP patients (p = 0.043). Patients with OA showed significant differences when comparing their BW with HSs (p = 0.001), with cLBP patients (p = 0.025) and CWP patients (p = 0.021). The BMI revealed significant differences between HSs and OA patients (p = 0.001) and HSs and patients with CWP (0.025).Significant differences concerning the height of all our patients were found between CWP patients and OA patients (p = 0.001). OA patients had significantly higher SMM compared to all other groups . BFM was significantly different between HSs and OA patients (p = 0.004) as well as HSs and CWP patients (p = 0.017). Regarding BWM, significant differences between OA patients and other groups were observed . OA patients indicated significant differences from all groups concerning their FFM . It was testified that our HSs had significantly less BFP than all our chronic pain patients . In addition to this, the WHR of our HSs was significantly lower than in all of our other groups as well .As expected, HSs had significantly less pain on the VAS compared to all chronic pain patients. Furthermore, OA patients showed significantly less pain compared to CWP patients , cLBP (p = 0.023), and CWP (p = 0.002) patients.Several immune cells were also compared and analyzed . Only CD+ CD8+ T cells, double positive T (DPT) cells (p = 0.031), CD3− CD56bright natural killer cells (NK) (p = 0.049), and CD20+ CD3− B cells (p = 0.007).Comparing total pain patients  with HSs  revealedThe results  showed sSubgrouping the numbers of patients according to HADS-A and HADS-D scores revealed unexpected results . More thp = 0.023). There was no other statistical difference between BDNF and immune cells.Subgroup analysis based on the anxiety score is demonstrated in + CD3− of cLBP patients. Furthermore, post hoc analysis showed a significant difference in the immune cell numbers of cLBP patients between a depression score ≤7 and ≥11 (p = 0.017), although after Bonferroni corrections, the level of significance was not reached (p = 0.052). There was no significant difference with regard to BDNF and immune cells in the cumulative group of patients  numbers yielded a significant negative correlation. In cLBP patients, anxiety and depression scores revealed positive correlations with pain intensity. In CWP patients, anxiety and depression scores revealed a positive correlation with pain intensity. Biological mediators did not show any significant correlations with clinical parameters in CWP patients.The aim of this study was to determine the pathomechanisms of different chronic pain patients, particularly by investigating BDNF.p < 0.05).Comparing OA, cLBP, and CWP patients and HSs, there were no significant differences concerning BDNF. Interestingly, comparing the collected data of all patients, the levels of free and total BDNF were significantly lower than in HSs  . In this2 or BMI > 25 kg/m2. We found that our patients had an average BMI of 27.68 ± 0.92 and that 35.1% of our CWP patients showed high scores of anxiety and 10% a high score of depression.Our patients showed not only remarkably higher body composition parameters but also psychological problems compared to HSs. Mood disorders are more likely to develop in patients with chronic pain . The stuIt is known that central sensitization can lead to intensified pain , and an + CD56+ NK cells between FMS patients and HSs [− CD56bright NK cells showed a significant difference between groups. To our knowledge, there are no studies reporting CD3− CD56bright NK cells and free BDNF in patients with chronic low back pain. Additionally, we found that OA patients with depression showed a significant negative correlation with CD3− CD56bright NK cells. Therefore, the higher the level of depression, the lower the amount of these specific immune cells. To date, CD3− CD56bright NK cells have not been investigated in patients with osteoarthritis (in knees or hips) in combination with depression. However, there are studies researching the connection of depression with natural killer cells and other studies focusing on the amount of natural killer cells in osteoarthritis [− CD56bright NK cells, but rather NK cells in general, there seems to be a connection between depression and NK cells. In a study of Wang et al. [bright CD16− NK subset in OA patients was augmented and that CD56bright CD16− NK cells from OA patients had reduced regulatory functions.In addition to BDNF, we explored different types of immune cells in these groups of patients. Previous studies have shown significant differences in the CD3 and HSs . In thisrthritis . Majidi-g et al. , natural− CD56bright NK cells revealed significant differences. It is known that patients suffering from cLBP or patients with musculoskeletal problems show a lower percentage of NK cells than asymptomatic subjects [Comparing all chronic pain patients to HSs, CD3subjects . Additiosubjects .+ CD8+cells and CD20+ CD3− (B) cells while comparing all chronic pain patients with HSs. It is known that T lymphocytes not only have a promoting effect on chronic pain, but they also play a role in the transition from acute to chronic pain [Another significant difference was found in CD4nic pain . Interesnic pain  has showWith regard to the BDNF levels and immune cell numbers based on anxiety scores in the different chronic pain diseases, a significant difference was found exclusively in the level of free BDNF in OA patients. There does not seem to be a study investigating BDNF and anxiety scores in patients suffering with OA, but there are several studies on BDNF and mood disorders . As mentThis study has some limitations. The ratio between females and males was not equal among the groups. Most of the patients were female, especially in the group of CWP patients. However, this reflects the prevalence of these groups of patients . As mentA general conformity between the pathomechanisms of different chronic pain diseases seems to exist, although there are unique findings only in specific chronic pain groups, as observed in BDNF and analyzed immune cells, particularly NK cells. Our results also highlight that the wider the region of the pain, the higher severity  the patients experience.


Primary outcome was the level of pain on a visual analogue scale (VAS 0–10) at 3/6/12/18 months, secondary outcomes were patient-related outcome measures , grip strength, patient’s satisfaction, and Dupuytren’s disease progression over 18 months follow-up. Focused ESWT significantly improved outcomes. Pain was reduced from 3.6 ± 1.8 to 1.9 ± 1.2 at three, to 1.4 ± 0.7 at six, to 1.7 ± 1.6 after 12 months and 1.9 ± 0.8 after 18 months in the intervention group . In the placebo group, pain on VAS increased from 2.2 ± 1.4 to 3.4 ± 1.7 at three, to 3.4 ± 1.8 at six, to 3.4 ± 1.4 at 12 and 3.1 ± 1.1 at 18 months . Quality-of-life score tended to improve in the intervention group  while it deteriorated in the placebo group as Dupuytren’s disease was progressing . The strength of the affected hand and fingers did not change significantly in either of the groups. Patients’ satisfaction was higher in the intervention group for symptom improvement (56% vs. 12%) and reduction of disease progression (59% vs. 24%). Any Dupuytren-related intervention was performed in 26% in the intervention group and in 36% in the placebo group within 18 months of follow-up (n.s.). Focused electromagnetic high-energetic ESWT can significantly reduce pain in painful nodules in Dupuytren’s disease in an 18-month perspective. .Dupuytren’s disease is a progressive fibroproliferative disorder of the hand. In the nodular stage of Dupuytren’s disease, pain might limit daily hand activities and progress to finger contractures. Focused electromagnetic high-energetic extracorporeal shockwave therapy (ESWT) may reduce pain in Dupuytren’s nodules (Tubiana N). In this prospective, randomized, blinded, placebo-controlled single center trial, we enrolled 52 patients  with painful nodular Dupuytren disease Tubiana N. Randomization was done to either (group A) 3 treatments with focused electromagnetic high-energetic ESWT (2000 shots, 3 Hz, 0.35 mmJ/mm Dupuytren’s disease is a progressive fibromatosis of the palm and flexor side of the hand with similar, but more rare manifestations located on the dorsal PIP joints as knuckle pads (aka Garrod’s nodules)  2], at , at 2], When dealing with Dupuytren’s disease, one should differentiate the nodular initial stage from established cords with contractures, since treatment recommendations differ substantially between these two entities . While oFrom a histological point of view, Dupuytren nodules contain whorls of collagen bundles and are densely packed with contractile fibroblasts and myofibroblasts . These hCarla Stecco described  a signifExtracorporeal shockwave therapy (ESWT) as a noninvasive therapy is using acoustic waves characterized by a sharp, abrupt, and rapid change in pressure as a wave front with a velocity higher than the speed of sound followed by a longer negative tail to elicit a body response. Since the first clinical report on successful kidney stone resolution by high-energetic focused electrohydraulic ESWT on Dec 13, 1980 in The Lancet by Chaussy , a substClinicalTrials.gov NCT01184586).Based on these aforementioned observations, we hypothesized that focused high-energetic ESWT can reduce pain on painful Dupuytren nodules. To answer this scientific question most adequately, we chose a prospective randomized-controlled study design .The study was approved by the IRB at Hannover Medical School. The RCT is directed according to the ethical principles of Good Clinical Practices. It is registered at DUPUYSHOCK is a prospective, single center, randomized, blinded, placebo-controlled clinical trial with 1:1 parallel group randomization.n = 27) or the placebo-treatment group  or cords without flexion contractures were enrolled. The Tubiana classification—first published in 1961 —distinguAll patients provided written informed content. Prior to initiating treatment, the investigator identified up to three primary nodules or cords in one hand for treatment in each patient. Criteria were size of the nodule and level of pain most patients felt in this state of Dupuytren’s disease.Eligible patients are patients aged 18 or over and 80 or youngerPainful Dupuytren’s disease of Tubiana stage N (nodular) and 1 involving one or more fingers or the palm onlyInclusion criteria:Exclusion criteria are suspected or evident pregnancyNo painful Dupuytren’s diseaseEvident ulcerationsNo informed consentAge under 18 years or above 80 yearsExclusion criteria:2 per week) or SHAM-ESWT treatment .Patients were randomly assigned in a 1:1 ratio to either treatment with high-energetic focused electromagnetic extracorporeal shockwave therapy .Extracorporeal shockwave therapy (ESWT) is using acoustic waves with a sharp, abrupt, and rapid change in pressure as a wave front with a velocity higher than the speed of sound followed by a longer negative tail to elicit a body response . GeneralOn February 8, 1980, the first clinical application of extracorporeal shockwave therapy has been performed in Munich, Germany for kidney stone lithotripsy  27]..27].Electrohydraulic generatorElectromagnetic generatorPiezoelectric generatorFrom a physical point of view, focused technologies involve different generators to elicit a focused shockwave:In this study, a focused electromagnetic ESWT device (Storz Duolith SD1) was used which is composed of a cylindrical coil and a parabolic reflector. A coil excites a cylindrical membrane, which generates a wave that is focused, similar to lithotripsy spark sources, by a parabolic reflector. Focused ESWT should be differentiated from radial pressures waves, which are generated either by air pressure like an air gun or by electromagnetic coils.2) should be described which are defined as  or SHAM focused ESWT (0.01 mJ/mm2) with 2000 shots per session. A treatment cycle comprised three ESWT treatments in week 0, 1, and 2, each tied to previous examination and surveys. Follow-up examination occurred 3 months after the last treatment, continued by follow-up surveys and further questioning after 6, 12, and 18 months  at follow-up 3, 6, 12, and 18 months after the last focused shockwave treatment.The primary end point of this randomized controlled trial (RCT) was a The DASH score  29]29]The Michigan Hand questionnaire (MHQ)   31]31]The Unite Rhumatologique des Affections de la main (URAM) scale As secondary endpoints we chose validated patient-orientated outcome measures, as such as follows:The DASH score  consists of 30 questions on activities such as “open a tight or new jar,” “write,” “turn a key,” “prepare a meal,” and others with the patient rating on the difficulty level of such activities from 1 = no difficulty, over 2 = mild difficulty, 3 = moderate difficulty, 4 = severe difficulty, and 5 = unable to do so. The higher the score, the stronger is the deterioration of the affected upper limb. Likewise, the Michigan Hand questionnaire askes 25 unilateral and 12 bilateral questions on activities of the upper extremity. Last, the URAM scale with 9 questions was originally designed for advanced Dupuytren’s disease with contractures undergoing percutaneous needle fasciotomy. Thus, the URAM scale was evaluated in advanced Tubiana 1° or higher stages in the original description. In nodular stage like in our study, this URAM scale has not been described yet.The GERMAN-DASH The German-MHQ German-URAM  accordinFor language-purposed, we used the validated German translated versions of the following:improvement of function measured with self-reported hand function and disability assessed by the Disabilities of Arm Shoulder and Hand Questionnaire (DASH).An change of the patient-related outcome measure Michigan Hand questionnaire (MHQ)A change of the patient-related outcome measure URAM [A ure URAM Hand grip strength [kg] was measured using a JAMAR dynamometer in three repetitions on each hand with elbow fully extended prior to every treatment and after the third treatmentPatient satisfaction and progression of Dupuytren’s diseaseAs such, the secondary endpoints were as follows:Monitoring of potential adverse effects was done. In case of local adverse events, patients had the opportunity to directly contact the investigator. No severe adverse events were reported during the entire study period of this RCT.The statistical analysis examined the difference between the high-energetic focused ESWT and the SHAM focused ESWT (between-effect) and the repetition of measurements over the period of time (within-effect) in each patient. Metric variables were depending on the different instruments used. Mixed analysis of variation (ANOVA) had to be applied. Based on the small size of groups, standard distribution could not be taken as a basis. Accordingly, the target variable had to be transformed into a normal score via rank transformation and then converted by inverse normal transformation (INT). Afterwards, a correction of the degrees of freedom according to Greenhouse-Geiser (or Huynh-Feldt) was applied.Eight patients of each group had to be excluded from the analysis because of missing participation in follow-up evaluation or undergoing surgery within the period of evaluation.The statistical analysis of the pain measured with VAS shows a significant effect over the time as it shows of intervention. A significant effect over time but no effect of intervention in DASH and URAM was shown and no significant effects regarding time or intervention in MHQ.p < 0.05).In the intervention group , pain levels were significantly reduced from 3.6 ± 1.8 to 1.9 ± 1.2 (−47%) at 3 months, to 1.4 ± 0.7 (−61%) at 6 months, to 1.7 ± 1.6 (−53%) after 12 months, and to 1.9 ± 0.8 (−47%) after 18 months in the intervention group  while it deteriorated in the placebo group as Dupuytren’s disease was progressing  18 months after treatment  was improved in the intervention group from 77 ± 19 to 83 ± 12, while it deteriorated in the placebo group as Dupuytren’s disease was progressing  while it deteriorated in the placebo group as Dupuytren’s disease was progressing (1 ± 2 to 3 ± 2). However, this was not significant.The strength of the affected hand and fingers did not change significantly in either of the groups Table .Table 2SPatients’ satisfaction was higher in the intervention group for improvement of symptoms (56% vs. 12%) and reduction of disease progression (59% vs. 24%). Any Dupuytren-related intervention was performed in 26% in the intervention group and in 36% in the placebo group (n.s.)  is an effective and safe noninvasive treatment to reduce the pain in the early nodular stage of Dupuytren’s disease. Three focused ESWT sessions could demonstrate a significant pain reduction and a sustained effect over 18 months of follow-up in this randomized-controlled trial.This finding should be discussed in detail. The nodular stage of Dupuytren’s disease is a condition which may impair activity of daily living, for example, during push-up exercises, Yoga exercises or during homework. Traditionally, the nodular stage of Dupuytren’s disease Tubiana N has not been addressed therapeutically as extensive as the Dupuytren cords at least in an evidence-based medicine point of view. Given the progressive nature of the disease, it is tempted to focus even early on in this progressive disease which might help reducing morbidity and mortality in a long-term perspective.Nonetheless, a number of different therapeutic options have been highlighted for the nodular stage of Dupuytren’s disease; however, from an evidence-based medicine point of view, on cohort study levels mainly. Radiotherapy has been proposed since the 1980s especially in Germany for early stage of Dupuytren . RandomiWe found that three sessions of focused electromagnetic ESWT can reduce pain over a period of 18 months significantly. By now, a number of potential beneficial effects of ESWT on various tissues have been reported, such as a stem cell propagation , growth A possible additional ESWT mechanism with regard to the aforementioned pain reduction in our RCT is an anti-fibrotic effect via the TGF-beta signaling pathway Fig. .Fig. 8PoTGF-ß is a master regulator of fibrosis . The proThus, it is tempting to speculate that the observed pain reduction in the ESWT intervention group with the strongest pain reduction 6 months after three focused ESWT sessions might be at least mediated by antifibrotic effects.In addition, an anti-inflammatory effect of ESWT has been described in a number of studies  48]. Fr. Fr48]. It is tempted to speculate that even an interaction of ESWT and nerves might play a role in this regard. Murata  studied While we could show a significant reduction of pain following three sessions of focused electromagnetic high-energetic ESWT, we failed to show a statistically significant improvement of the secondary outcome parameters as patient-related outcome scores. We believe this is due to the often only mild changes or impairments early stage of Dupuytren’s disease is causing reflected by our patient cohort with very low scoring in the patient-related outcome measures DASH, MHQ, and URAM. All questionnaires included  revealed at baseline only mild changes from normal in our patient cohort (DASH mean 12 points (0–100); MHQ 78 points (0–100)); therefore, the potential benefit of a given intervention (here focused high-energetic ESWT) might be hampered by the only mild nature of impairment. For the DASH, the minimal clinically important difference has been reported to be 11 points in an Italian study and 15 points by the DASH authors . We obseFor the Michigan Hand Questionnaire (MHQ), this so called “ceiling effect” has been reported by the founder of the MHQ, Kevin Chung  with poiFocused electromagnetic high-energetic ESWT can significantly reduce pain in painful nodules in Dupuytren’s disease. No adverse effects were noted.