Nonverbal pain cues such as facial expressions, are useful in the systematic assessment of pain in people with dementia who have severe limitations in their ability to communicate. Nonetheless, the extent to which observers rely on specific pain-related facial responses  when judging pain remains unclear. Observers viewed three types of videos of patients expressing pain  while wearing an eye tracker device that recorded their viewing behaviors. They provided pain ratings for each patient in the videos. These observers assigned higher pain ratings to older adults compared to younger adults and the highest pain ratings to patients with dementia. Pain ratings assigned to younger adults showed greater correspondence to objectively coded facial reactions compared to older adults. The correspondence of observer ratings was not affected by the cognitive status of target patients as there were no differences between the ratings assigned to older adults with and without dementia. Observers’ percentage of total dwell time  across specific facial areas did not predict the correspondence of observers’ pain ratings to objective coding of facial responses. Our results demonstrate that patient characteristics such as age and cognitive status impact the pain decoding process by observers when viewing facial expressions of pain in others. Observers tend to decode another’s pain experience by interpreting verbal and nonverbal cues  in older faces could affect the interpretation of facial expressions by observers such that pain-related cues may be more difficult to discern and decode making pain judgments harder to evaluate compared when observing younger faces  incorporate key components of pain expressiveness  for our analyses. Observers were 164 undergraduate students  with a mean age of 21 years (SD = 5). One hundred and thirty-two of our observers reported having close contact with an older adult ranging from daily to less than monthly contact. Two additional observers were not included in the final sample due to technical difficulties with the eye tracker device. Observers were primarily recruited from the department of psychology’s subject pool. An effort was made to recruit comparable numbers of male and female observers. Observers received either course credit or monetary compensation ($10) for participation and provided informed consent as approved by our Institutional Ethics Review Board.Power analyses, assuming alpha = .05 and power level = .80, determined 158 observers would provide more than adequate power to detect small to medium effects  to 5 . Eyelid closure is coded as absent (0) or present (1). A pain expression index is then constructed by summing the individual action codes. It can vary from 0 to 16 . The sampling rate of the sensors is 500 Hz and has an accuracy of less than 0.5 degrees with respect to the visual angle. Each observer wore the eye tracker device, which was calibrated to each individual and re-calibrated as necessary during testing. The device tracked and recorded the viewing behaviors of the observers while they watched the stimulus videos in order to discern which specific nonverbal pain cues, contained within facial areas of interest, were being viewed and the corresponding total duration of time the observers gazed at these cues.“Dwell time” is defined as the amount of time that an observer glances or fixates within a facial area of interest,“Total dwell time” refers to an observer’s total dwell time amount between all facial areas of interest,“Percentage of total dwell time for each specific area of interest” is defined as the proportion of dwell time an observer spends in one area of interest in relation to all areas of interest.More specifically, the faces of the pain patients in the stimulus videos were segmented into areas of interest containing the facial cues of pain including: forehead, brows, eyes, cheeks, nose, mouth, and a non-specified other region. The non-specified other region refers to any other area in the video that did not contain any facial cues of pain. These areas correspond to the scores derived from the FACS-based method described by Prkachin and Solomon , as prevNot intense at all” to “Most intense”. The VAS is a single-item scale that measures subjective experiences such as pain and has been widely used in adult populations  and completed a demographic questionnaire. Subsequently, each observer had the EyeLink II eye tracker device properly calibrated before testing. All observers took part in each of the three study conditions, which included viewing the 30 stimulus videos. Observers were asked to view the videos while wearing the eye tracker device. They were also asked to provide observational pain intensity ratings for each of the patients in the videos through the use of 100 mm visual analogue scales (VASs) anchored by the polar opposites “While the observers viewed the video segments, the EyeLink II recorded their viewing behaviors and collected the corresponding data. Specifically, the eye tracker recorded the dwell time of the observer’s attendance to the previously outlined areas of interest containing the facial cues of pain and the percentage of total dwell time among the areas of interest. The eye tracker device was re-calibrated as needed in order to ensure that proper data collection was accomplished.Following examination of the interrater reliability of our FACS coding for our specific stimulus video set, we conducted a 2  x 3  analysis of variance (ANOVA) with FACS-based scores as the dependent variable. The aim of this analysis was to determine if the stimulus videos displayed comparable levels of facial expressiveness across video conditions.z = [x − x̄]/s where x̄ is the mean and s the standard deviation) in order to calculate observer rating-FACS correspondence indices. Using FACS scores as an objective index, observer pain rating correspondence scores were calculated  and averaged for each observer under each video condition. For example, in a case where a video had a FACS score of 7 and an observer VAS pain intensity rating of 52.60, we first converted the FACS score into a standardized score using the sample mean and standard deviation, (7–6.42)/3.44 = 0.17. A similar procedure was followed for the observer VAS pain intensity rating yielding a standardized value of 0.47. The correspondence score in this case, would be − 0.30 .Average observer pain intensity ratings, as well as the percentage of total dwell time among the areas of interest, were calculated for each observer under each video condition. The observer VAS pain intensity ratings and FACS scores were standardized using z-score conversion  X 3  within-subjects ANOVA was run. A similar analytic approach was used with observers’ correspondence scores as the dependent variable.For all ANOVAs, Mauchly’s tests were conducted to test the assumption of sphericity. When this assumption was violated, degrees of freedom were corrected using the Greenhouse–Geisser correction and the Huynh–Feldt correction as appropriate. For all significant main effects, Bonferroni post hoc tests were conducted.Regression analyses were conducted to examine whether the percentage of observers’ total dwell time among the target areas of interest  predicted observer pain rating correspondence scores. For each regression, the following variable was used as a predictor: observers’ percentage of total dwell time for each interest area. One regression was conducted across all video conditions, and additional regressions were conducted specifically within each video condition. In all cases, the regressions were used to predict observer correspondence (to FACS coding). Bonferroni corrections were applied to the four regression analyses resulting in an adjusted alpha level of .01.Correlation coefficients were calculated to examine the relationship between observers’ visual behavior within the areas of interest containing facial pain cues and the intensity of these pain cues as coded using our FACS-based index. One sample t-tests examined whether observer pain correspondence scores in relation to FACS scores were significantly different from zero (zero scores would be indicative of perfect correspondence). Positive scores that are significantly higher than 0 would indicate underestimation of pain while negative scores would indicate overestimation.Finally, for exploratory purposes, additional 2  X 3  within-subjects exploratory ANOVAs were conducted to examine differences in observer fixation to facial pain cues as a function of video condition using dwell time within the non-specified other region , as well as dwell time within the remaining target facial areas of interest as dependent variables. Bonferroni correction was applied to the exploratory ANOVA analyses to correct for family-wise error rates resulting in an alpha level of .007.F = .584, p = .580, partial η2 = .127, 95% CI , target patient gender, F = .035, p = .860, partial η2 = .009, 95% CI , and the interaction between video condition and target patient gender, F = 2.97, p = .108, partial η2 = .426, 95% CI , were not significant. Table Interrater reliability on our specific set of videos was 0.92 for the global FACS-based score which was used in our analysis . The stimulus video segments all showed comparable levels of facial pain intensity (based on FACS scores) such that there were no significant differences in pain expressions across video conditions or target patient gender. This was determined by the 2 (target gender) X 3 (video condition) within-subjects analysis of variance (ANOVA) that compared the non-verbally displayed pain intensity (as measured by the aforementioned coding approach) across the three video conditions and target patient gender. The main effect of video condition, F = 106.24, p < .001, partial η2 = .395, 95% CI . There was also a significant interaction between target patient gender and video condition, F = 9.36, p < .001, partial η2 = .054, 95% CI . The main effect of target patient gender was not significant, F = 1.25, p = .264, partial η2 = .008, 95% CI .Observer pain ratings are presented in Fig. MD = 9.14 (SE = .76), p < .001, 95% CI , and to younger adults, MD = 11.29 (SE = .89), p < .001, 95% CI . Pairwise comparisons also demonstrated a significant difference between pain intensity ratings assigned to older adults without dementia and younger adults such that observers rated the pain of older adults without dementia as more intense, MD = 2.15 (SE = .81), p = .025, 95% CI . Additional pairwise comparisons suggested that among patients with dementia, females were assigned greater pain ratings than males, MD = 2.12 (SE = .92), p = .022, 95% CI . Among younger adults, females were also assigned greater pain ratings than males, MD = 2.02 (SE = .83), p = .016, 95% CI . However, among older patients without dementia, males were assigned greater pain ratings than females, MD = 2.43 (SE = .83), p = .004, 95% CI .Follow-up pairwise comparisons indicated that observers assigned greater pain intensity ratings to older adults with dementia compared to both older adults without dementia, 95% CI 7.9, 10.99,F = 86.67, p < .001, partial η2 = .347, 95% CI . The main effect of target patient gender was also significant indicating that ratings for female patients showed greater correspondence to objective coding compared to ratings for male patients, F = 13.49, p < .001, partial η2 = .076, 95% CI . There was also a significant interaction effect between target patient gender and video condition, F = 14.50, p < .001, partial η2 = .082, 95% CI .Pain rating correspondence scores are presented in Fig. MD = − 0.26 (SE = .02), p < .001, 95% CI , and older adults without dementia, MD = − 0.23 (SE = .02), p < .001, 95% CI . There were no significant differences between observer correspondence scores for older adults with dementia and older adults without dementia. Follow-up pairwise comparisons also suggested that among patients with dementia, ratings assigned to females corresponded more to objective coding than those assigned to males, MD = − 0.15 (SE = .03), p < .001, 95% CI . Among younger adults, ratings assigned to females corresponded more to objective coding than ratings assigned to males, MD = − 0.10 (SE = .03), p < .001, 95% CI . However, there were no significant differences between males and females among older patients without dementia.Follow-up pairwise comparisons indicated that observers’ ratings for younger adults showed greater correspondence compared to ratings for older adults with dementia, F = 0.87, p = .530, R2= .038, and the three video conditions,  did not yield significant results either. Contrary to Hypothesis III, observer dwell time proportioned among the target facial areas of interest did not significantly predict observer pain rating correspondence in reference to FACS scores.In order to examine whether observers’ percentage of total dwell time among the areas of interest  predicted observer pain rating correspondence scores, multiple linear regression analyses were conducted. Four regression analyses were performed on observer pain rating correspondence scores . Prior to conducting the regression analyses, intercorrelations between dwell time among the areas of interest and correspondence scores were calculated. We adopted a conservative significance level of .01 due to the large number of intercorrelations. None of these exploratory intercorrelations were statistically significant. Regression analyses regarding the full models for overall observer pain rating correspondence, One sample t-tests were conducted to test if observer pain rating correspondence scores in relation to FACS scores were significantly different than a score of zero, which would indicate perfect correspondence. Results of the t-tests are presented in Table r = 0.508, p < .01. Observers’ fixation to the nose area of interest was negatively correlated with levator contraction, r = − 0.371, p < .05. Observers’ fixation to the brows area of interest was not significantly correlated with brow lowering, r = − 0.007, p > .05. Finally, observers’ fixation to the eyes area of interest was not significantly correlated with orbit tightening, r = 0.275, p > .05.Correlations were also calculated to examine the relationship between observers’ percentage of total dwell time within specific areas of interest containing facial pain cues and the intensity of these facial pain cues as coded using our FACS-based approach. Specifically, the areas of interest examined were: eyes, brows, and nose, as these areas of interest contain the four facial cues most often associated with pain expression. These cues include: brow lowering, orbit tightening, levator contraction, and eye closure. Observers’ fixation to the eyes area of interest was positively correlated with eye closure, F = 167.85, p < .001, partial η2 = .507, 95% CI . The main effect of target patient gender, F = 0.05, p = .828, partial η2 = .000, 95% CI , and the interaction effect between video condition and target patient gender, F = 2.67, p = .079, partial η2 = .016, 95% CI , were not significant. Follow-up pairwise comparisons indicated that the area containing no facial pain cues was looked at more when viewing older patients with dementia compared to older patients without dementia, MD = 0.06 (SE = .00), p < .001, 95% CI , and younger patients, MD = 0.06 (SE = .00), p < .001, 95% CI .Mean values and SDs are presented in Table F = 39.48, p < .001, partial η2 = .195, 95% CI . As the Bonferroni correction was applied resulting in an alpha level of .007, the main effect of video condition, F = 3.69, p = .027, partial η2 = .022, 95% CI , and target patient gender, F = 1.29, p = .257, partial η2 = .008, 95% CI , were not significant. Follow-up pairwise comparisons suggested the brow area was looked at more when viewing females among patients with dementia, MD = 0.02 (SE = .01), p < .001, 95% CI , and younger adults, MD = 0.01 (SE = .01), p = .014, 95% CI . Among patients without dementia, the brow area was looked at more when viewing males, MD = 0.04 (SE = .01), p < .001, 95% CI .The second 2 (target patient gender) X 3 (video condition) within-subjects ANOVA was conducted to examine effects on observers’ dwell time within the brow area of interest. The results of this ANOVA revealed a significant interaction effect between video condition and target patient gender, F = 77.39, p < .001, partial η2 = .322, 95% CI . There was also a significant interaction effect between video condition and target patient gender, F = 189.13, p < .001, partial η2 = .537, 95% CI . The main effect of target patient gender was not significant, F = 1.62, p = .205, partial η2 = .010, 95% CI . Follow-up pairwise comparisons indicated that the cheek area was looked at more when viewing older patients with dementia compared to older patients without dementia, MD = 0.03 (SE = .00), p < .001, 95% CI , and younger patients, MD = 0.01 (SE = .00), p < .001, 95% CI . The cheek area was also looked at more when viewing younger patients compared to older patients without dementia, MD = 0.01 (SE = .00), p < .001, 95% CI . Additional pairwise comparisons suggested the cheek area was looked at more when viewing females among patients without dementia, MD = 0.01 (SE = .00), p = .004, 95% CI , and younger adults, MD = 0.04 (SE = .00), p < .001, 95% CI . Among patients with dementia, the cheek area was looked at more when viewing males, MD = 0.05 (SE = .00), p < .001, 95% CI .The third 2 (target patient gender) X 3 (video condition) within-subjects ANOVA was conducted to examine effects on observers’ dwell time within the cheeks area of interest. The results revealed a significant main effect of video condition, F = 43.40, p < .001, partial η2 = .210, 95% CI  There was also a significant main effect of target patient gender, F = 26.83, p < .001, partial η2 = .141, 95% CI  with the eye area being looked at more when viewing male patients. Finally, there was also a significant interaction effect between video condition and target patient gender, F = 29.34, p < .001, partial η2 = .153, 95% CI . Follow-up pairwise comparisons indicated that the eye area was looked at less when viewing older patients with dementia compared to older patients without dementia, MD = − 0.04 (SE = .01), p < .001, 95% CI , and younger patients, MD = − 0.06 (SE = .01), p < .001, 95% CI . The eye area was also looked at more when viewing younger patients compared to older patients without dementia, MD = 0.02 (SE = .01), p = .023, 95% CI . Additional pairwise comparisons suggested the eye area was looked at more when viewing males among patients with dementia, MD = 0.03 (SE = .01), p < .001, 95% CI , and younger adults, MD = 0.07 (SE = .01), p < .001, 95% CI . Among patients without dementia, the eye area was looked at more when viewing females, MD = 0.03 (SE = .01), p = .005, 95% CI .The fourth 2 (target patient gender) X 3 (video condition) within-subjects ANOVA was conducted to examine effects on observers’ dwell time within the eyes area of interest. The results revealed a significant main effect of video condition, F = 69.60, p < .001, partial η2 = .299, 95% CI . There was also a significant main effect of target patient gender with the forehead area being looked at more when viewing males, F = 31.66, p < .001, partial η2 = .163, 95% CI . Finally, there was also a significant interaction effect between video condition and target patient gender, F = 105.29, p < .001, partial η2 = .392, 95% CI . Follow-up pairwise comparisons indicated that the forehead area was looked at more when viewing older patients without dementia compared to older patients with dementia, MD = 0.04 (SE = .00), p < .001, 95% CI , and younger patients, MD = 0.05 (SE = .01), p < .001, 95% CI . There were no significant differences in dwell time between older patient with dementia and younger adults. Additional pairwise comparisons suggested the forehead area was looked at more when viewing females among patients with dementia, MD = 0.01 (SE = .01), p = .011, 95% CI , and younger adults, MD = 0.03 (SE = .01), p < .001, 95% CI . Among patients without dementia, the forehead area was looked at more when viewing males, MD = 0.10 (SE = .01), p < .001, 95% CI .The fifth 2 (target patient gender) X 3 (video condition) within-subjects ANOVA was conducted to examine effects on observers’ dwell time within the forehead area of interest. The results revealed a significant main effect of video condition, F = 25.14, p < .001, partial η2 = .134, 95% CI . There was also a significant main effect of target patient gender, F = 9.03, p = .003, partial η2 = .052, 95% CI , with the mouth area being looked at more when viewing females. The interaction effect between video condition and target patient gender, F = 0.87, p = .411, partial η2 = .005, 95% CI , was not significant. Follow-up pairwise comparisons indicated that the mouth area was looked at more when viewing younger patients compared to older patients with dementia, MD = 0.02 (SE = .00), p < .001, 95% CI , and older patients without dementia, MD = 0.01 (SE = .00), p = .001, 95% CI . The mouth area was also looked at more when viewing older patients without dementia compared to older patients with dementia, MD = 0.01 (SE = .00), p < .001, 95% CI .The sixth 2 (target patient gender) X 3 (video condition) within-subjects ANOVA was conducted to examine effects on observers’ dwell time within the mouth area of interest. The results revealed a significant main effect of video condition, F = 30.00, p < .001, partial η2 = .155, 95% CI . There was also a significant main effect of target patient gender, F = 78.64, p < .001, partial η2 = .325, 95% CI  such that the nose area was looked at more when viewing female patients. Finally, there was a significant interaction effect between video condition and target patient gender, F = 91.24, p < .001, partial η2 = .359, 95% CI . Follow-up pairwise comparisons indicated that the nose area was looked at more when viewing younger patients compared to older patients with dementia, MD = 0.05 (SE = .01), p < .001, 95% CI , and older patients without dementia, MD = 0.02 (SE = .01), p = .039, 95% CI . The nose area was also looked at more when viewing older patients without dementia compared to older patients with dementia, MD = 0.03 (SE = .01), p < .001, 95% CI . Additional pairwise comparisons suggested the nose area was looked at more when viewing females among patients with dementia, MD = 0.03 (SE = .01), p = .001, 95% CI , and patients without dementia, MD = 0.13 (SE = .01), p < .001, 95% CI . Among younger adults, the nose area was looked at more when viewing males, MD = 0.05 (SE = .01), p < .001, 95% CI .The last 2 (target patient gender) X 3 (video condition) within-subjects ANOVA was conducted to examine effects on observers’ dwell time within the nose area of interest. The results revealed a significant main effect of video condition, Observers’ fixation patterns to facial pain cues as well as pain judgments varied as a function of patient characteristics, including age and cognitive status . That is, older people were viewed as having more pain than younger individuals and older adults with dementia were viewed as having more pain than other patients. Gender differences were identified such that pain inferences differed as a function of target patient gender. These results contribute to our understanding of pain communication , possibly because this allows for a holistic perception of the face due to their peripheral vision allowing them to peripherally detect the facial pain cues. That said, correlational results also indicated that observers dwelled more on the eyes when patients displayed the eye closure facial cue, but dwelled less on the nose when the levator contraction pain cue was more intense, possibly due to observers not requiring much time to recognize this intense facial reaction. Observers may also be relying on other contextual factors such as emotional expressions of the face or on their own knowledge regarding pain in others. Of note, spontaneous facial pain expressions conveyed during the physiotherapy examination (which was designed to identify painful areas) allowed for the study to have greater ecological validity compared to studies of experimentally induced pain.Findings from exploratory analyses examining observer dwell time among the target facial areas of interest containing facial pain cues suggested that observers’ viewing behavior varied as a function of video condition and target patient gender. Future studies are needed to determine the meaning of these results if such findings are replicated. Furthermore, findings indicated that observers looked less at facial pain cues when viewing older adults with dementia compared to older adults without dementia and younger adults. This difference in dwell time duration to facial pain cues could be due to a preference for fixating on faces seen as more physically attractive, as is often the case with younger faces (Foos and Clark Prior research has shown that observer characteristics influence the pain decoding process (Hadjistavropoulos et al. Health care professionals and caregivers may infer a patient’s pain through several pain behaviors (Labus et al. This investigation provided further understanding of the relationship between nonverbal pain behaviors and observer inferences regarding pain in others, specifically individuals with dementia. As well, differences were found in observers’ viewing behaviors such that observers spent less time gazing at facial pain cues for individuals with dementia. These findings also added to our understanding of influences on observers’ decoding of pain (Hadjistavropoulos et al.


Social touch is important for interpersonal interaction. Gentle touch and slow brushing are typically perceived as pleasant, the degree of pleasantness is linked to the activity of the C-tactile (CT) fibers, a class of unmyelinated nerves in the skin. The inability to experience pleasure in general is called anhedonia, a common phenomenon in the chronic pain condition fibromyalgia. Here, we studied the perception and cortical processing of gentle touch in a well-characterized cohort of fibromyalgia. Patients and controls participated in functional brain imaging while receiving tactile stimuli (brushing) on the forearm. They were asked to provide ratings of pleasantness of the tactile stimulus and ongoing pain. We found high distress, pain catastrophizing, and insomnia, and a low perceived state of health in fibromyalgia. Further, patients rated both slow  and fast  brushing as less pleasant than healthy participants. While there was no difference in brain activity during touch, patients showed deactivation in the right posterior insula  during pleasantness rating and activation during pain rating. The opposite pattern was observed in healthy participants. Voxel-based morphometry analysis revealed reduced grey matter density in patients, in the bilateral hippocampus and anterior insula. Our results suggest anhedonia to gentle touch in fibromyalgia with intact early-stage sensory processing but dysfunctional evaluative processing. These findings contribute to our understanding of the mechanisms underlying anhedonia in fibromyalgia. Fibromyalgia (FM) is a common, debilitating chronic pain condition. According to the American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia .Social touch is important for human behavior and communication between individuals . PleasanWhile unmyelinated nociceptors have been the focus of earlier studies on fibromyalgia , less isCT-optimal touch produces robust activation of the posterior insula with a somatotopic organization similar to that reported for cutaneous and muscle pain in healthy participants ,10. FM pIn the current study, we hypothesized to find differences in neural processing in the insular cortex, in response to CT-optimal touch in FM. In a group of well-characterized FM patients, we used fMRI to examine the cortical responses to slow and fast brush stroking and compared with matched healthy controls. In parallel, ratings for touch pleasantness and ongoing pain were collected. Grey matter density was also measured.Female patients with a clinical diagnosis of FM, ranging between 25–55 years old, were recruited through the Pain and Rehabilitation Center at the Linköping University Hospital. These patients were recruited as part of a broader characterization of FM. Age- and gender-matched healthy controls (HC) were recruited through advertisements at the Linköping University and the University Hospital, and in the local news media. The Linköping Regional Ethics Review Board approved the study (Dnr 2016/471-32) and written informed consent was obtained after participants had read the complete study description, in accordance with the Declaration of Helsinki.2) was calculated as weight/height2. At the time-point of the clinical examination, the subjects answered a health questionnaire covering demographic data as well as pain and psychological characteristics.On the first visit, all participants underwent a clinical examination. To confirm the patients’ eligibility, the eighteen tender points according to the FM classification criteria of the American College of Rheumatology  were cliExclusion criteria were MRI-incompatibility , pregnancy, difficulty understanding Swedish, metabolic disease, neurological disease or severe psychiatric conditions, malignancy, rheumatoid arthritis, unregulated thyroid disease, cardiovascular disease, or lung disease. Another exclusion criterion was the inability to refrain from analgesics, including NSAIDs and sleep medication, for 48 h prior to the fMRI visit . Participants in the HC group reported having no current pain.Functional imaging data of good quality were obtained for 31 patients  and 29 matched controls (mean age 42.7 ± 10.1 years).Age and gender were registered. FM patients also reported the duration of their condition in years.A numeric rating scale (NRS) with anchor points 0 (denoting no pain) and 10 (denoting the worst imaginable pain) was used to capture the current pain (denoted by ‘Pain Intensity Current’) and the average pain intensity for the previous four weeks (denoted by ‘Pain Intensity 4w’).The Hospital Anxiety and Depression Scale (HADS) was used to measure symptoms of anxiety and depression. The validated Swedish translation of HADS was chosen to reflect aspects of psychological distress ,15 and hThe Insomnia Severity Index (ISI) was used to quantify perceived insomnia severity. ISI captures the severity and impact of insomnia symptoms with good validity and internal consistency ,18. The PCS measures three dimensions of catastrophizing—rumination, magnification, and helplessness ,20—basedAn NRS with anchor points 0  and 10 (denoted impossible to perform these activities) was used to capture to what extent the pain hindered daily activities (pain hindrance activities of daily living (ADL)), taking part in leisure activities including social and family activities (pain hindrance leisure), and working, including studies or homework (pain hindrance work). These items were only answered by the FM group.EQ-5D captured a patient’s perceived state of health ,23,24. TParticipants were asked to report their ongoing pharmacological treatments. Note that those included in the study were asked to refrain from analgesic use, including NSAIDs and sleep medication, for 48 h prior to the fMRI visit.Before entering the MRI scanner, participants were instructed that they will be brushed on the forearm and were shown the rating scales. They were also brushed once on the forearm. During MRI, participants were brushed on the left forearm at two different velocities—3 cm/s  and 30 cm/s . The brusher, who was trained in the delivery of these stimuli, stood next to the scanner bore and received auditory cues over headphones. A 9-cm long line with 3-cm increments, was marked on the left forearm to aid the brusher to maintain the correct speed. The task consisted of three runs of 6 min each. In between runs, the participants were asked if they were alright in the scanner and okay to continue with the next run. In total, there were 15 repetitions of slow and fast brushing blocks, each lasting 12 s. The intertrial interval (ITI) between blocks was 10 to 12 s. The order of brushing velocities was randomized. During ITIs, participants looked at a fixation cross. Three times per condition (slow or fast), following a 10 to 12-s ITI, a question appeared on the screen asking the participant to rate the pleasantness of the brushing (“How pleasant is the stimulus?”) and if they felt any pain (“Do you feel any pain?”). We formulated the latter question in this specific way because we assumed it might be difficult for the FM group to disentangle ongoing pain and specific pain related to the stimulus. This rating was therefore to be understood as rating of any ongoing pain. Using a button box in their right hand, participants moved a cursor on a visual analog scale (VAS) between the endpoints “unpleasant–pleasant” or “no pain–intense pain” (in Swedish). During analysis, the cursor positions were converted to their numerical values, ranging from −10 to +10 for pleasantness and 0 to 20 for pain. The pain ratings were not specifically related to brush-evoked sensation but to the subjects’ general pain level.Participants laid comfortably in a 3.0 Tesla Siemens scanner . Their left arm was placed on their belly and propped up by pillows. A 12-channel head coil was used to acquire 295 T2-weighted echo-planar images (EPI) per run, containing 48 multiband slices . T1-weighted anatomical images were also acquired.p-values < 0.05 were considered significant.Behavioral data were analyzed using SPSS . Ratings for slow and fast blocks were averaged. Ratings of the patient group were normally distributed; ratings of the control group were not due to a strong ceiling effect. Ratings were compared between conditions using paired t-test (FM) and Wilcoxon test (HC), and between groups, using Mann–Whitney U test. http://www.fil.ion.ucl.ac.uk/spm) in Matlab R2016a . The following steps were performed—motion correction, co-registration of the mean EPI and the anatomical image, spatial normalization to the MNI T1 template, and segmentation of the T1 image, using the unified segmentation approach [Functional MRI data were analyzed using statistical parametric mapping  was estimated using the VBM routine provided by the CAT12 toolbox  in SPM12. Total intracranial volume was included as a covariate. Groups were compared using a The disease duration in the FM cohort was 4.4 years, on average, since diagnosis and as expected, they had a high number of tender points, i.e., at the group level, >16 out of 18. In HC, the tender points were scarcely found. FM patients had significantly higher blood pressure and BMI than HC. While HC reported no pain, both pain intensity measures (current and at 4 weeks) in FM patients were above 5 on the NRS. Distress, pain catastrophizing, and insomnia  were significantly higher and overall health (EQ-VAS) was significantly lower in FM patients .Four FM patients had more severe symptoms (≥11) according to the HADS-Depression subscale, compared to none in the HC. Corresponding figures for the HADS-Anxiety were eight patients in FM and none in HC. At least moderate insomnia (≥15) was found in 14 FM patients and in one HC.n = 19), antidepressant medication , tricyclic antidepressants (n = 9), opioids (n = 7), vitamins , medication for high blood pressure (n = 3), proton-pump inhibitors (n = 3), gabapentin (n = 2), antihistamine (n = 2), and other medications (n = 9). HC reported sumatriptan (n = 1), tricyclic antidepressant (n = 1), methotrexate (n = 1), and metoprolol (n = 1). All participants refrained from analgesics including NSAIDs and sleep medication for 48 h prior to the fMRI visit (cf. Methods).Three FM patients and 26 HC did not use any pharmacological drugs. Those using medication among the FM cohort were often on several substances (range 1–5), including paracetamol  . There wSince we found a difference in ratings between HC and FM, we also explored group differences during the rating period. Activation in posterior insula was related to whether the subjects were rating on the pleasantness or the pain scale A. While VBM analysis comparing HC and FM revealed reduced grey matter density in patients in the bilateral hippocampus and anterior insula. This difference was even stronger when including age as a covariate of no interest . There wIn the current study, we found intact neural processing of positive affective touch in FM patients. However, slow soft brushing was reported as less pleasant by FM patients than healthy controls. We found that FM patients differed from HC during the rating of perceived pleasantness and pain. FM patients showed deactivation in the right posterior insula during the pleasantness rating and activation during the pain rating, the opposite pattern of what was observed in the HC.The pathophysiology of FM is not well-understood. Both peripheral and central nervous system alterations are involved in the development and maintenance of FM. Hence, alterations in the brain including neuroinflammation and activation of glial cells, nociception-driven amplification of neural signaling , opioidergic dysregulation, and impaired top-down modulation were found, as well as signs of systemic low-grade inflammation  and nociceptor and muscle protein changes ,38,39,40The finding that HC did not rate the pleasantness of slow and fast brushing differently needs further consideration. Although average pleasantness ratings were descriptively higher for slow than for fast brushing, they were not statistically different. Previous studies have reported that people rate slow, CT-optimal brushing velocities as more pleasant than fast, CT-non-optimal brushing ,26,42. HWe found differential processing during the evaluative period for the two groups and conditions. While HC showed activation in posterior insula during pleasantness evaluation and deactivation during pain evaluation, FM showed deactivation during pleasantness evaluation and activation during pain evaluation. This result should be considered preliminary as it was the result of an exploratory analysis. That the cluster of the interaction effect did not directly overlap with the main effect of slow versus fast touch was not surprising, since the evaluative processing of the current experience was a different, hierarchically higher processing, and might therefore have involved different clusters within the insula ,46,47,48FM patients display hyper-sensitivity to a range of sensory stimuli , so it hAlterations in grey matter in many brain regions related to pain processing have been reported in several studies (for review see ). These The hippocampal grey matter is decreased in people suffering from stress  and postThere are several limitations that need to be considered when interpreting our results. FM is a condition of highly varied symptoms and severity; therefore, patient samples tend to be heterogeneous. Larger and longitudinal studies are needed to distinguish subgroups within FM. Here, we focused on brushing for its affective attribute and link to C-tactile fibers, and questionnaires to capture the clinical characteristics, but we did not perform a detailed battery of quantitative somatosensory tests ,71,72; tTaken together, our results suggest intact early-stage sensory processing of positive tactile stimuli but dysfunctional evaluative processing. These findings contribute to our understanding of the mechanisms underlying anhedonia in FM.


Continuous subcutaneous infusion (CSCI) via ambulatory infusion pump (AIP) is a valuable method of pain control in palliative care. When using CSCI, low-dose methadone as add-on to other opioids might be an option in complex pain situations. This study aimed to investigate the effects, and adverse effects, of CSCI for pain control in dying patients, with particular interest in methadone use.This was an observational cohort study. Imminently dying patients with pain, admitted to specialized palliative inpatient wards and introduced on CSCI, were monitored daily by staff for symptoms , sedation , performance status (Eastern Cooperative Oncology Group - ECOG) and delirium (Confusion Assessment Method - CAM).p < 0.001) after starting CSCI, with only a moderate increase in morphine equivalent daily dose of opioids (MEDD). Alertness was marginally decreased , whereas performance status and prevalence of delirium, regardless of age, remained unchanged.Ninety-three patients with a median survival of 4 days were included. Of the 47 patients who survived ≥3 days, the proportion of patients with severe/overwhelming pain decreased from 45 to 19% (n = 13) and patients with only other opioids , improved in pain control , despite that MET patients had higher pain scores at baseline (p < 0.05) and were on a higher MEDD (240 mg vs.133 mg). No serious adverse effects demanding treatment stop were reported.Both patients with methadone as add-on (MET, CSCI via AIP is an effective way to reduce pain in dying patients without increased adverse effects. Add-on methadone may be beneficial in patients with severe complex pain. Pain is a common clinical problem in palliative care . Eighty Low-dose add-on peroral methadone in combination with other opioids for pain is proposed to be a useful alternative to methadone therapy for better pain control at the end of life –12. The Whereas patient-reported outcomes are encouraged, this is not possible in imminently dying patients, as the majority of them are not able to complete a questionnaire for obvious reasons, such as, terminal delirium, extreme tiredness or lowered level of consciousness. For this reason, very few studies on symptoms and symptom control have been performed in the very last days of life, a period which is important both for the patient and for their families. A way to overcome this problem is to use validated instruments allowing proxy measures, e.g. assessments made by staff.The primary aim of the study was to report the effects on pain intensity and occurrence of adverse effects, e.g. sedation, confusion, and respiratory depression, when prescribing an AIP for CSCI in imminently dying patients. A secondary aim was to specifically study the effects of the addition of low-dose methadone to a CSCI comprising another opioid in this patient group.The methods and results sections are reported, when applicable, based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria .At the specialized palliative care in-patient unit at Stockholm Sjukhem Foundation, we conducted an observational cohort study in patients who were prescribed CSCI via AIP for symptom management during the last days of life. Patients were included from February 1, 2019 to January 22, 2020 and followed up daily, with the last follow-up on January 28, 2020.All Swedish-speaking patients over the age of 18 years who were neither sedated nor unconscious and who, during daytime (7 am – 8 pm) as part of their regular care, were prescribed a CSCI of drugs were asked to participate in the study. Inclusions were not possible during other hours due to limited available resources for performing the inclusion procedure.The total cohort consisted of all patients that were included. The main study group consisted of those patients from the main study group, who had pain at inclusion and who survived for three days or more.For every patient, baseline data on age, sex, indication for CSCI, prevalence, intensity and type of pain were registered. Daily registrations covered the previous 24 h and included medications, site of SC infusion, skin irritation around the SC needle, and other symptoms including patient anxiety, alertness, performance status and occurrence of confusion.As the patients were in an acute dying phase with rapid deterioration from day to day, the study applied exclusively instruments allowing proxy measures (staff measures). The daily assessments were performed by the registered nurse responsible for the patients’ care on that day and could thus be performed by various individuals from day to day. The proxy version of the Integrated Palliative Care Outcome Scale (IPOS) was used to assess the patient’s symptoms and relatives’ concerns . The IPOThis is a descriptive study, and no sample size calculation was performed.Descriptive statistics are presented with both means and medians as appropriate. T-tests were used to compare age and survival, and, for other variables, the following non-parametric tests were applied: chi-square test to compare proportions, Mann–Whitney U test to compare independent groups and Wilcoxon signed-rank test to compare dependent groups.From initiation of CSCI until day 3, there were missing data on an average of 5 patients per day of the total study cohort, though in no case for more than one consecutive day. For missing data, the last observation carried forward was used. Analysis was performed using SPSS Version 26.Ethical approval (2018/2103–31/1) was obtained from the Regional Ethical Review Board  and all participants consented to inclusion in the study.During the study period, 321 patients were prescribed CSCI and a total of 93 were included in the study intended to be followed prospectively. Of those not included, 88% were assessed as too ill to give formal consent and 12% abstained . For further characteristics, see Table Thirty-three patients (70%) used peroral non-opioids and/or adjuvant analgesics on the day of initiation of CSCI (mean 1.7 adjuvants), including corticosteroids, paracetamol (acetaminophen), NSAIDs, antidepressants and gabapentinoids. The following opioids  were used in the main study group until the switch to CSCI: Oxycodone in 61% of the cases, morphine in 23%, fentanyl patches in 14% and hydromorphone in 2% of the cases. All oral opioids were discontinued upon conversion to CSCI. The total mean morphine equivalent daily dose (MEDD) via CSCI at baseline was 184 mg. In eight cases, only opioids were used in the AIP, in 17 cases the opioids were combined with one additional drug, in 16 cases with two others and in six cases with three other drugs. For specific details on CSCIs containing methadone, see Table p < 0.001) and the mean pain score from 2.2 (median 2) to 1.5 (median 2) on the five-point pain IPOS scale, (Table The proportion of patients severely or overwhelmingly affected by pain decreased from 45 to 19% (p = 0.001), (Table p = 0.31) and performance status did not change significantly.The mean level of alertness went from − 0.2 to − 1.2, i.e. 1 point on a 10-point scale , Table . During Delirium was seen in 30% of the patients at day 0 and did not change significantly over time (day 0 vs. day 3). Neither were there differences between patients under or above 75 years of age, Table .p = 0.04), , (Table Thirteen patients received low-dose methadone added to the continuous infusion (MET). The median time of survival from initiation of CSCI was 14 days for the MET group compared with 4 days for the group of patients whose CSCIs contained no methadone (NMET), respectively , Table . All thep = 0.004). From days 0 to 3 there was an increase in opioid doses for NMET (p = 0.02).At baseline, the MEDD of opioids via CSCI for MET (median 240 mg) was almost twice the dose for NMET (median 133 mg), (p = 0.02) and a higher proportion of severe/overwhelming pain, 77% vs. 32% (p = 0.009),  and the proportion of severe pain was lower, . The levels dropped from 0.4 to − 0.9  and from − 0.4 to − 1.3 , respectively, , performance status, anxiety, or prevalence of delirium, . However, the clinical impact is probably minor as the change was 1.0 in a 10-grade scale, i.e. a 10 % deterioration, in acutely dying patients. Besides this, there were neither any increase in intensity of other adverse symptoms nor any serious adverse effects that demanded specific interventions. Moreover, we observed no significant differences over time or between MET and NMET regarding performance status, anxiety levels or doses of the anxiolytic midazolam. These observations agree with the general observation that adverse effects such as sedation, constipation, and respiratory depression are associated with the pharmacology of opioids as a class, and similar reactions are expected regardless of route [There was a statistically significant decrease in alertness . We described a similar difference in a study from 2020 on a different sample [There was a significant difference in mean age between the MET group, 68 years, and the NMET group, 78 years, (t sample . To the We do recognize some limitations of the study. First, as accounted for in the methods section, all patients receiving a CSCI were not included, usually due to illness and of ability to provide informed consent, as well as some patients refraining from participation. Second, as methadone, according to clinical guidelines, was mainly prescribed to patients with the most severe pain, the MET and NMET groups differed significantly at baseline as regards pain intensity and MEDD. Still, such comparisons of subgroups are of interest, as they reflect a clinical reality. Comparable control groups are difficult to achieve in a population of dying patients in need of parenteral drug administration, and randomization with control groups is seldom possible, for ethical reasons. Third, due to the severe illnesses of the patients, observer ratings had to be used. By definition, observer assessment may not directly reflect the patient’s experiences, meanwhile, they allow studies in the last days and hours of life, on an important patient group that is often excluded from studies. The assessments were based on subjective judgements by the registered nurses who performed the registrations. Consequently, the assessments came to a certain extent to depend on each individual’s level of knowledge, skills, and personal attitudes. Finally, this is a single-center study reflecting the experiences at one particular setting.Strengths include the prospective design until death and the use of validated instruments for symptom assessments. Another strength is that the proxy assessments were performed by trained personnel, which may have contributed to improved assessments of adverse effects .Regardless of age, CSCI via AIP for pain seems effective in reducing pain in dying patients without any substantial increase of adverse effects such as delirium or respiratory depression. An addition of low-dose methadone may be beneficial for CSCIs for patients with severe cancer pain at the end of life. The effectiveness of low-dose methadone in combination with the patient’s regular opioid needs further investigation, preferably with a randomized controlled trial.


As it is less known about the prevalence and characteristics of pain in the patients with interstitial lung disease (ILD), this paper aims at determining the characteristics of the pain in the patients with ILD.Subjects with ILD and health controls with the matched ages and genders completed Short Form McGill Pain Questionnaire (SF-MPQ) and part of the Brief Pain Inventory (BPI) Short Form to elicit the characteristics of the pain. The patients with ILD were also assessed through Pulmonary Function Test, Six Minutes Walking Test (6MWT), modified Medical Research Council Dyspnea Scale (mMRC) for state of the illness and measured health-related quality of life (HRQoL) by Short Form-36 (SF-36) and psychological associations by Hospital Anxiety and Depression Scale (HADS).A total of 63 subjects with ILD and 63 healthy controls (HC) were recruited in our study. The prevalence of the pain was 61.9% in ILD versus 25.3% in HC (P = 0.005) and the median score of the pain rank index (PRI) in ILD was higher than that in HC (P = 0.014). Chest (46.1%) accounted for the highest of overall pain locations in subjects with ILD. Associated clinical factors for pain intensity in the patients with ILD included exposure history of risk factors of ILD, with a longer distance of 6MWD (≥ 250 m), and a higher mMRC score (2–4). The patients with ILD and pain are more likely to suffer impaired HRQoL (P = 0.0014) and psychological problems .The pain is common in those with ILD and the pain intensity is associated with exposure history, 6MWD, and mMRC score. The patients with ILD and pain were possibly to suffer depression, anxiety, and impaired HRQoL. Interstitial lung diseases (ILDs) refer to a complex and large group of diseases that are typically characterized by the basic pathological changes of diffuse lung parenchyma, alveolar inflammation, and interstitial fibrosis with substantial morbidity and mortality , 2, whicIn 2020, the current International Association for the Study of Pain (IASP) defined pain as “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damages” . DepressGiven the limited treatment options available to the patients with ILD, it is important to accurately identify and optimally manage coexisting conditions. A better understanding of the characteristics of pain and its influences on symptoms and physical activities will help inform approaches for prognosis of ILD. The objectives of this study were to determine the characteristics of pain  in patients with ILD compared with healthy, age and gender-matched control participants, the patients with ILD complicated with other respiratory disease and explore the association between pain, dyspnea, physiology function, psychological symptoms and quality of life.This cross-sectional study used routinely collected data from the Second Xiangya hospital of central south university, a tertiary hospital in Changsha, Hunan province of China, between January of 2019 and January of 2020. This study was approved by the Medical Ethical Committee of the Second Xiangya Hospital of Central South University(Approved Number KL-2014-S009), and all participants gave written informed consent.The ILD patients were sequentially selected from among those under hospitalization and treatments at the Second Xiangya Hospital. Inclusion criteria for the ILD group included 1) met with diagnosis criterion of ILD  met withAll subjects attended for 1 visit, at which time the following measures were undertaken:Information recorded in the registry included demographic details . Pain assessment by the Short Form McGill Pain Questionnaire (SF-MPQ) and part of the Brief Pain Inventory (BPI) Short Form: SF-MPQ was used to evaluate the pain intensity of subjects, scores of different parts of SF-MPQ were calculated to characterize the pain problems –17. SF-MThe subjects with ILD also completed the following measures:Whether there was a history of exposure to risk factors related to ILD, the pulmonary function test (PFT) to investigate the lung volume compartment and pulmonary diffusing capacity, according to standard criteria –22. Six Continuous variables were described as mean (SD) if they were normally distributed or as median (IQR) if they were not, and categorical variables were described as counts and percentages (%). Comparisons between groups  for continuous measurements were analyzed using paired t-tests, independent t-test or Kruskal–Wallis H test, with categorical data analyzed using Chi Square test. The statistical analyses were conducted using SPSS (Version.25) software . P < 0.05 was considered as statistically significant.From January 2019 to December 2019, a total of 141 potential subjects with ILD and 100 healthy controls were approached  patients with ILD and pain, 14 (35.9%) was diagnosed as IPF, 22 (56.4%) was CTD-ILD and 3 (7.7%) were other ILD (two patients with NSIP and one patient with IIP). The pain locations in 14 IPF patients distributed in chest (57.1%), joint (21.4%), back (14.3%) and limb (7.1%) and in 25 non-IPF patients distributed in chest (40.0%), joint (24.0%), limb (20.0%), back (8.0%), abdomen (4.0%) and the other parts (4.0%), including head and lumbar vertebra . Besides, the subjects with ILD and pain showed more anxious and depression according to the HADS, in anxious dimension 23 (59.0%) patients with pain and 21 (87.5%) patients without pain were assessed for no case, 16 (41.0%) patients with pain and 3 (12.5%) patients without pain were assessed for borderline or case (P = 0.017); in depression dimension 23 (59.0%) with pain vs 20 (83.3%) without pain were assessed for no case, 16 (41.0%) with pain vs 4 (16.7%) without pain were assessed for borderline or case (P = 0.044). From the different dimensions of HRQL measured by RAND-36, HRQL were significantly impaired in patients with ILD and pain which can be found in SF Total score , and also performed in mental health (p = 0.029), bodily pain (P = 0.049), vitality (P = 0.043), and role emotional dimension (P = 0.006).In the ILD Group Table, 39  and joint (23.1%) among all the patients with ILD and pain. 57.1% of the patients with IPF and pain declared having chest pain, which was higher than non-IPF (40.0%). Kaisa’s study  also fouILD Group experienced a higher pain intensity than HC Group both in feeling and emotion dimension. A higher intensity of pain in the patients with ILD was also associated with many factors in our study, including exposure history of ILD risk factors, longer distance of 6MWD (≥ 250 m), higher mMRC score (2–4) and impaired SF-36 and HAD score. When undergoing severe dyspnea, the patients normally gave extra worse results of pulmonary function test, especially FVC, % predicted and DLCo, % predicted, and unsatisfied 6WMT, a practical and reliable measure of exercise tolerance that was widely used to assess the functional status of the patients with IPF , which s. Therefore, those indicated the need of healthcare providers, clinicians, and patients to pay greater attention to the patients with ILD and pain and consider strategies to minimize their impacts on the patients’ quality of life, healthcare utilization, and prognosis.The patients with ILD and pain suffered worse quality of life and psychological deficits, like symptoms of anxiety and depression , 45. TheTo our knowledge, this is the first study to investigate pain in patients with ILD, including the intensity, location, type and associated factors. However, generalizability beyond this specific group and setting is limited, as only 126 subjects from one hospital were included, there are some limits in our study results to a single time-point and does not allow us to describe the changes in pain or symptoms over time. Our study may be subjected to some selection bias and as some patients at a very advanced stage of the disease or close to death were likely to be lost from the cohort. Possibilities of false negative due to small sample size and false positive due to multiple testing. Another limitation is that the score of this questionnaire may be mixed with subjective feeling, especially the VAS score, and effected by individual verbal comprehension. The last but not the least, what was the accurate cause of pain in the patient with ILD couldn’t be completely sure in our study. In the future, a larger sample of cross- sectional or cohort studies may be conducted on factors related to pain intensity to further verify these results.In conclusion, pain is common in the patients with ILD and the pain intensity is associated with exposure history, 6MWD, and mMRC score. The patients with ILD and pain have more possibility to suffer depression, anxiety and impaired HRQoL. Knowledge of pain in ILD and intervention measures should be developed for both patients and clinicians about the pain management to improve the health-related quality of life at early stages of ILD.Additional file 1: Table S1.Exclusion criteria of participants.


Introduction: Although transcranial direct current stimulation (tDCS) and mirror therapy (MT) have benefits in combating chronic pain, there is still no evidence of the effects of the simultaneous application of these techniques in patients with neuropathic pain. This study aims to assess the efficacy of tDCS paired with MT in neuropathic pain after brachial plexus injury.Methods: In a sham controlled, double-blind, parallel-group design, 16 patients were randomized to receive active or sham tDCS administered during mirror therapy. Each patient received 12 treatment sessions, 30 min each, during a period of 4 weeks over M1 contralateral to the side of the injury. Outcome variables were evaluated at baseline and post-treatment using the McGill questionnaire, Brief Pain Inventory, and Medical Outcomes Study 36–Item Short-Form Health Survey. Long-term effects of treatment were evaluated at a 3-month follow-up.Results: An improvement in pain relief and quality of life were observed in both groups (p ≤ 0.05). However, active tDCS and mirror therapy resulted in greater improvements after the endpoint (p ≤ 0.02). No statistically significant differences in the outcome measures were identified among the groups at follow-up (p ≥ 0.12). A significant relationship was found between baseline pain intensity and outcome measures (p ≤ 0.04). Moreover, the results showed that state anxiety is closely linked to post-treatment pain relief (p ≤ 0.05).Conclusion: Active tDCS combined with mirror therapy has a short-term effect of pain relief, however, levels of pain and anxiety at the baseline should be considered.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT04385030. Brachial plexus injury-related neuropathic pain is a complex chronic complication with a broad variety of structural and functional brain changes involved –3. PatieTranscranial Direct Current Stimulation (tDCS) is increasingly used to treat refractory chronic pain –8. It isIt has been suggested that combining tDCS with a rehabilitative protocol for pain can foster the effects of single treatments . Given tThirty participants with brachial plexus lesions were recruited from public health units from September of 2019 to December of 2019. This study was conducted in accordance with the principles of the Helsinki Declaration. All subjects gave informed consent in a written form, according to the protocol approved by the Institutional Ethics Committee.Participants were assessed for eligibility based on the following inclusion criteria: age over 18 years; chronic neuropathic pain for at least 3 months following traumatic plexus injury; a pain intensity of at least 4 out of 10 in the numerical rating scale; stable pharmacological treatment for at least 1 month prior to the study and throughout the study. The diagnosis of a traumatic brachial plexus lesion was based on clinical criteria based on motor, sensory, and autonomic deficits –25 and chttps://www.random.org/. Group allocations were sealed in opaque envelopes, which were kept by a third-party researcher. The same staff member, who was blind to the treatment interventions, performed all clinical evaluations. An independent researcher, who applied the interventions, remained blind to the findings of the clinical evaluation. Patients were masked to treatment allocation and the hypotheses of the study.A randomized, controlled pilot trial was conducted, wherein participants admitted consecutively were assigned to 1 of 2 treatment groups (1:1 ratio): active tDCS plus MT or sham tDCS plus MT. Registration and randomization were centralized via a web-based system This paper has been presented according to the CONSORT guidelines  29). Du. Du29). In the baseline visit, we performed the structured questionnaire including demographic data, injury characteristics, affected side, pain severity, symptoms of depression, and anxiety. Pain severity was evaluated with a Visual Analog Scale . The BecThe primary and secondary outcomes were applied at baseline and post-treatment. The score change in McGill Questionnaire (MPQ) was the primary endpoint of our study. The McGill Questionnaire is a multidimensional instrument that evaluates various aspects of pain: sensory, affective, evaluative, and miscellaneous. The quantitative data is summed to form the Pain Rating Index (PRI) with a score rating from 0 to 78, lower scores reflecting more desirable conditions .The secondary outcome measures were pain related to daily activities and quality of life. The Brief Pain Inventory (BPI) was designed to measure both the intensity of pain and the interference of pain on daily activities. The four severity items and the seven interference items can also each be averaged to form the Pain Severity Index and the Pain Interference Index . Quality2 surface sponge electrodes soaked in a saline solution (0.9% sodium chloride). The anodal electrode was placed over C3 or C4  and the reference electrode was fixed on the contralateral supraorbital area. Sham tDCS was applied with the same configuration, but the current lasted only 30 s.All of the patients received tDCS stimulation, starting at the beginning of MT, over M1 contralateral to the side of injury . Each paThe intervention was delivered 3 days per week and all sessions were performed at the same time of the day, in the same quiet room. Participants were seated close to a table on which a mirror (30 × 45 cm) was placed vertically . The invpost-hoc Dunn-Sidak adjustment. Mann–Whitney U-test was run for pairwise comparison. Further, we determined the overall effect size using Kendall's coefficient of concordance (within-group change) and Cliff's delta test (between-group change). All tests were 2-tailed and differences were considered statistically significant at p < 0.05.An intention-to-treat analysis was applied during the study. Comparisons of the baseline characteristics between groups were analyzed using the chi-squared and Fisher's test. K-related samples Friedman test was applied to study the effect of tDCS on such variables over time, with Due to many factors that may influence pain level and quality of life after treatment, we adjusted the value in a linear regression model with the stepwise method, which tested the influence of age, duration of illness, pain severity (VAS score), and baseline depressive symptoms (BDI score). We also included anxiety (using STAI-S) as a covariate because pain and quality of life may be affected by state anxiety level. We tested single effects for treatment (active tDCS plus MT and sham tDCS plus MT) and anxiety levels, and interaction between treatment and pain severity at baseline, followed by Bonferroni correction and univariate linear regression analyses where significant main effects were found. To avoid baseline differences, we used deltas (Δ) based on the mean difference's calculation [(post-test–pre-test)/pre-test] for these analyses. All statistics were conducted using Statistical Package for Social Sciences v21 .Sixteen patients were randomly assigned to one of two study groups (active tDCS + MT and sham tDCS + MT). Only one patient failed to complete the entire study. Both active intervention and sham were well-tolerated. Two patients in the active treatment group described a transient mild tingling or a slight itching sensation associated with the onset of stimulation .The pain thresholds obtained from the MPQ points to a significant difference between groups, which followed the same trend: a reduced perception of pain after treatment when compared to the baseline. However, there was an apparent benefit to the active tDCS+MT group over the sham tDCS+MT group at the endpoint. The perception of pain relief was not maintained after 3-month for both groups . The chaResults from the ANOVAs examining session effects for BPI scale are shown in The quality of life post-treatment was significantly increased for both groups at the endpoint. However, comparisons between the baseline and the 3-month evaluation showed an improvement in SF-36 scores only in the active tDCS+MT group . Figure p < 0.05).We investigated how group factors and covariates are associated with primary and secondary outcomes, using univariate linear regression analyses as parameter estimates . As can The present double-blind, sham-controlled pilot study provides evidence that tDCS combined with mirror therapy promotes analgesia in multidimensional aspects, reducing the severity and interference of pain with daily activities, as well as improving quality of life levels in patients with neuropathic pain. Interestingly, the effects of active tDCS on primary and secondary outcomes were partially dependent on baseline levels of pain and anxiety. However, these benefits were not maintained in the long-term (3-month follow-up). As far as we know, this is the first study to assess the effects of tDCS paired with physical therapy in patients with brachial plexus injury.Our results are similar to previous studies that found synergistic effects of tDCS and mirror therapy in pain relief and increased quality of life in other clinical conditions , 39, 40.When considering the interaction between treatment and the pain and anxiety levels at baseline, it becomes clear that these variables had important effects in the group that received active tDCS and mirror therapy. It has been indicated that both the pain and anxiety levels are variables that modify treatment efficacy in patients with chronic pain . SimilarWe also found that treatment effects were dependent on the pain level at baseline in relation to the quality of life. The difference here is that, unlike the primary outcome measured by the McGill questionnaire, this association was not only present for the active group, whose tests presented a larger effect size. Although it is not clear why this relationship was also observed in the sham group, when we consider these associations, it should be noted that patients in this group also received an intervention arm of mirror therapy. Thus, for the quality of life construct (which has different factors from those that compose the pain component), how much pain the patient has before starting treatment should probably also be considered when applying mirror therapy, regardless of whether it is associated with neurostimulation.Our results did not show benefits in pain and quality of life being maintained at follow-up for both groups. We can speculate that the duration of therapy we employed  may not be sufficient to induce significant long- term retention effects in patients with neuropathic pain. Studies with other populations show lasting visual illusion benefits in reducing pain , suggestAlthough the present study may bring important considerations for non-invasive treatment in patients with neuropathic pain, these findings should be viewed with caution for some reasons. For example, in the present work, we did not employ neuroimaging or computational modeling techniques to control cortical changes. In order to minimize this bias, we controlled the eligibility criteria, performed randomization among the groups and, used statistical inferences to weigh possible moderations of variables associated with response prediction. In a complementary way, it is worth mentioning that these inferences are also limited due to the lack of a healthy control group and a placebo mirror therapy protocol. In addition, we had a predominantly male sample, which limits our conclusions to this gender, although it should be noted that brachial plexus avulsion has a higher prevalence in males , 50. SmaOverall, our findings highlight two important conclusions. First, 12 sessions of anodic tDCS on the primary motor cortex combined with mirror therapy has a superior effect in promoting analgesia and improving quality of life compared to simulated stimulation and mirror therapy. The pain and anxiety levels before treatment had a relevant effect on our model when we considered the disability generated by neuropathic pain measured by the outcomes of the active group. These findings encourage developing studies involving multimodal therapies in other types of chronic pain and considering possible effect modifying variables.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Research Ethics Committee–Health Science Center–Federal University of Paraíba (CEP-CCS-UFPB). The patients/participants provided their written informed consent to participate in this study.EB, CF, CC, and RG: study conception and design. CF, CC, RG, and EB: data collection and analysis. SA, CM, CC, and RG: writing and/or critically revising the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background Brachial plexopathy causes pain and loss of function in the affected extremity. Entrapment of the brachial plexus terminal branches within the surrounding connective tissue, or medial brachial fascial compartment, may manifest in debilitating symptoms. Open fasciotomy and external neurolysis of the neurovascular bundle in the medial brachial fascial compartment were performed as a surgical treatment for pain and functional decline in the upper extremity. The aim of this study was to evaluate pain outcomes after surgery in patients diagnosed with brachial plexopathy.Methods We identified 21 patients who met inclusion criteria. Documents dated between 2005 and 2019 were reviewed from electronic medical records. Chart review was conducted to collect data on visual analog scale (VAS) for pain, Semmes-Weinstein monofilament test (SWMT), and Medical Research Council (MRC) scale for muscle strength. Pre- and postoperative data was obtained. A paired samplet-test was used to determine statistical significance of pain outcomes.Results Pain severity in the affected arm was significantly reduced after surgery . Additionally, there was an increased response to SWMT after the procedure. More patients achieved an MRC rating score ≥3 and ≥4 in elbow flexion after surgery. This may be indicative of improved sensory and motor function.Conclusion Open fasciotomy and external neurolysis at the medial brachial fascial compartment is an effective treatment for pain when nerve continuity is preserved. These benefits were evident in patients with a prolonged duration elapsed since injury onset. The brachial plexus is a complex network of nerves that transmits motor and sensory signals responsible for function of the upper extremity. Injury to the brachial plexus, known as brachial plexopathy, is most often a consequence of trauma.Brachial plexopathy is a complex and heterogenous condition that necessitates the use of a substantial amount of resources and a broad array of treatments for each unique patient. Many variables must be considered in the assessment and treatment of brachial plexopathy. These include but are not limited to patient demographics, mechanism of injury, comorbid injuries and medical conditions, severity and location of nerve lesion(s) as well as extent of plexus damage.Surgical interventions are generally reserved for cases refractory to conservative management. Advances in microsurgical techniques have spurred the development of techniques that effectively repair injured nerves. Notwithstanding, there remains continued debate regarding the diagnostic approach, timing of surgery, appropriate selection of surgical technique, and parameters for acceptable outcomes.Prior literature has revealed that only 19% of published articles on surgical techniques used in brachial plexopathy reported a pain outcome.We have identified an underreported source of neuropathic pain at the distal brachial plexus terminal branches. Several case reports have suggested that neuropathic pain can originate from compression of the terminal branches within the medial brachial fascial compartment (MBFC).The goal of the present study is to assess pain outcomes in patients diagnosed with brachial plexopathy who underwent open fasciotomy and external neurolysis at the MBFC. Our results demonstrate for the first time the effectiveness of this procedure at the MBFC in decreasing pain for patients diagnosed with nerve-in-continuity brachial plexus lesions.We conducted a retrospective chart review using the electronic medical records (EMR) at Baptist Hospital South Florida. Patients evaluated in clinic from 2005 to 2019 were identified by ICD-9 and ICD-10 codes in the EMR. The following ICD codes were required for inclusion: 953.4 , 353 , G54.0 , and S14.3 .Patients who fulfilled selection criteria were over the age of 18 years at the time of surgery, diagnosed with unilateral brachial plexopathy, and completed the present procedure. Patients who had obstetric complications, shoulder surgery, or other nerve repair procedures of the brachial plexus did not meet inclusion criteria. During chart review, we identified a total of 300 patients in our clinic who were given a diagnosis of brachial plexopathy. Of the 300 patients, 45 elected for surgical treatment and 21 met inclusion criteria for this study .Data collection included demographic information, surgical history, etiology, side of injury, dominant arm, interval from symptoms onset to surgery and from surgery to postoperative evaluation (≥6 months), visual analog scale (VAS) pain scores, Semmes-Weinstein monofilament test (SWMT) scores, and Medical Research Council (MRC) motor strength grades. VAS pain scores for only the brachium were recorded. SWMT results from the finger pulps were noted. MRC rating scores were assessed for elbow flexion, finger abduction, proximal interphalangeal joint (PIP)/distal interphalangeal joint (DIP) extension, and thumb abduction. All data were ascertained from documents dated before and after surgery. A minimum of 6 months elapsed from surgery was required for data inclusion. There were no limits on duration of injury prior to surgery. Clinical findings and surgical procedures were completed by the senior author.t-test.p-Values <0.05 were considered to be statistically significant. Descriptive analysis was performed to assess demographic data and compare MRC rating grades. MRC grades ≥ 3 and ≥ 4 were used as parameters for muscle strength.VAS and SWMT outcomes were analyzed for statistical significance using a paired samplePain unresponsive to conventional management was the single most important indication for surgery. Most patients were referred by specialists for “last ditch” management of neuropathic symptoms. Brachial plexopathy originating at the MBFC is a clinical diagnosis. The surgical indications and contraindications used in our clinic are demonstrated inAll practical steps should be conducted to rule out neurological, vascular, inflammatory etiologies of the cervical spine, shoulder, and arm. The differential diagnoses included cervical radiculopathy, nerve root avulsion, pre- or post-ganglionic nerve rupture, thoracic outlet syndrome, Parsonage-Turner syndrome, complex regional pain syndrome, shoulder impingement, rotator cuff tear, and biceps tendinopathy. Compression neuropathy at the MBFC is a diagnosis of exclusion.Electrodiagnostic studies were performed at third-party institutions as a continuation of clinical evaluation. Nerve conduction studies  and eleThe anatomy of the MBFC is illustrated inA total of 21 patients met inclusion criteria for this study.The median interval from symptoms onset to surgery was 11 months and 10 months from surgery to postoperative follow-up evaluation (>6 months). At the time of the procedure, the majority of patients underwent concurrent nerve release distally in the arm. Nerve decompression was performed at the cubital tunnel and carpal tunnel in 40% and 49% of patients, respectively.The VAS pain score was documented in the EMR for 21 patients, before and after surgery. A statistically significant reduction in VAS score was found when preoperative and postoperative values were compared. The mean preoperative VAS score was 6.4 (standard deviation or SD 2.5) and the mean postoperative VAS score was 2.0 (SD 2.5).p = 0.01), digit II (p = 0.03), digit III (p = 0.02), digit IV (p = 0.01), and digit V (p = 0.02).The SWMT score was analyzed for 21 patients, before and after surgery. SWMT is graded on a 1 to 5 scale and the score is interpreted as (1) normal, (2) diminished light touch, (3) diminished protective sensation, (4) loss of protective sensation, and (5) responsive only to deep pressure sensation. As shown inEach case of brachial plexopathy consists of a unique pattern of Sedon and Sunderland classifications of nerve injury. Despite the heterogenous nature of brachial plexus injury, a commonality among these patients is pain in the affected extremity. Pain stemming from nerve compression (often used interchangeably with “entrapment”) is particularly impervious to conservative management.A 47% reduction in pain was observed in patients who underwent open fasciotomy and external neurolysis at level IV of the brachial plexus. Prior work has demonstrated that a 30% decrease in pain intensity is a clinically significant treatment response.Excellent pain outcomes have been demonstrated from external neurolysis at common sites of compression of the median, ulnar, and lateral femoral cutaneous nerves. Narakas found adequate pain alleviation after neurolysis of intraneural and extraneural fibrosis throughout the entire brachial plexus.The MBFC spans from the neck to the proximal arm and consists of fibrous connective tissue that surrounds blood vessels and nerves of the brachial plexus. Within the compartment, there is loose connective tissue and cleavage planes that allow for longitudinal excursion of each nerve. In a study on cadavers with an unknown history of trauma, anatomical dissections of the brachial plexus sheath frequently unveiled scattered scar tissue throughout the semirigid compartment space.The histological changes commonly observed in chronic compression neuropathy include: intrafascicular edema, undulant demyelination and remyelination, altered myelin thickness, abnormal internodal length, apoptosis and proliferation of Schwann cells, altered expression of receptors and channels, as well as perineural and epineural fibrosis.Long-standing nerve compression does not preclude the ability for intrinsic repair if the impeding structure is adequately separated or removed with surgery. The timing of surgery may be key in nerve recovery but continues to be a topic of debate among experienced peripheral nerve surgeons, especially for certain techniques in nerve injury. The benefits of early intervention are twofold; to allow sufficient time for spontaneous nerve recovery and to prevent irreversible nerve damage.Although the role of external neurolysis was previously thought to be limited to pain relief, more recent evidence indicates that it has a sizeable impact on sensory and motor function recovery.An open surgical approach was used for all cases in this study. The importance of wide-exposure in compression-induced nerve lesions has been emphasized in the past. The brachial plexus is technically difficult to navigate during surgery because of the complex and intricate network nerves entangled with great vessels and connective tissue. Additionally, there is considerable anatomical variability within the MBFC that requires open exploration to comprehensively address each unique case. It is thought that minimally invasive techniques do not offer adequate visibility needed to engage all causative abnormalities within the distorted anatomical space.Future work should incorporate postoperative neurodiagnostic findings to quantify changes to electrical activity after surgery. Post-surgical EMG/NCS were not indicated in these cases and it is likely that most patients would have refused these studies. Thus, we were unable to objectively measure the neurophysiological effects of surgery as it pertains to changes in nerve structure and function. Socioeconomic and demographic factors may have impacted our data. All patients had private health care insurance and our results may not be reflected in an underserved population. Also, the majority of our patients were female even though a higher prevalence of brachial plexus injury has been established in males. A predilection of women to be treated by a female (the corresponding author) may have contributed to this finding. A prospective study using a handheld dynameter to quantify motor strength more precisely may also provide stronger data to support the present findings. The HSS questionnaire to measure impact of brachial plexus injury and assess surgical outcomes is a promising tool that will be used in our future research.The MBFC is prone to accumulating of scar tissue after trauma. Over time, the scar tissue can involve nerves of the brachial plexus resulting in a compression-induced dysfunction. We demonstrated successful pain, motor and sensory outcomes after external neurolysis for nerve-in-continuity lesions within the MBFC. Future investigations may further elucidate the benefits of this procedure when used in conjunction with distal nerve release. Our results support the utility of external neurolysis in patients with pain and nerve-in-continuity lesions of the terminal branches.


Osteoporosis and related complications have been increasing with the aging population. Osteoporotic vertebral compression fractures (OVCFs) are the most common among all osteoporotic fractures. The purpose of this study was performed to compare the efficiency and safety of vertebroplasty versus conservative treatment for acute OVCFs.The conduct of this study followed the Declaration of Helsinki principles and the reporting of this study adhered to the Consolidated Standards of Reporting Trials guidelines for randomized controlled trials. Written informed consent was obtained from every participant. Participants were randomly assigned (1:1) to receive either vertebroplasty or control group. The primary outcome was pain relief at 1 month and 1 year, measured with a Visual Analogue Scale score. The secondary outcomes were Roland-Morris Disability Questionnaire, short form score, European Quality of Life-5 Dimensions, and postoperative complications.We hypothesize that vertebroplasty will provide a rapid decrease of pain and an early return to daily life activities compared with the control group.This study protocol was registered in Research Registry (researchregistry5624). Vertebroplasty was first performed in a painful vertebral hemangioma case in 1984 in France. Its indication has been performed in trauma, osteoporotic fractures, malignant or benign spinal tumors, as well as vertebral osteonecrosis being modified in time. The most common area of usage is currently painful OVCFs. Vertebroplasty technic is a procedure involving the percutaneous injection of cement (polymethylmethacrylate) into the fracture line, with the help of a guide. The aim of this method is to increase the quality of life of the patient by reducing pain, eliminating the need to remain bedridden, and reducing the use of drugs.Osteoporosis and related complications have been increasing with the aging population. Osteoporotic vertebral compression fractures (OVCFs) are the most common among all osteoporotic fractures. OVCFs result in an increase of the incidence of mortality and morbidity, causes back/lumbar pain as well as kyphosis deformity, and reduces the quality of life. Conservative treatment is the initial treatment approach in this type of fracture.,5 However, the effect of percutaneous cement augmentation are unclear, as are the benefits of vertebroplasty and its adverse procedure-related events and incidence of adjacent compression fractures. Two randomized studies with a sham control intervention have reported clinical outcomes 1 month and 6 months after percutaneous vertebroplasty in patients with osteoporotic vertebral fractures up to a year old. Results of both studies seem to show that vertebroplasty and sham treatment are equally effective.,5Vertebroplasty, the injection of polymethylmethacrylate into the fractured vertebral body, is frequently used for symptomatic osteoporotic fractures, and is based on the premise that fracture stabilization can provide pain relief. It is a minimally invasive surgical technique first developed in the treatment of vertebral hemangiomas. Since its introduction, this minimally invasive technique has gained widespread recognition, effectively reducing pain both in the short and long term. The aim of this method is to increase the quality of life of the patient by reducing pain, eliminating the need to remain bedridden, and reducing the use of drugs.–11 We thus also designed a randomized controlled study to compare the efficiency and safety of vertebroplasty versus conservative treatment for acute OVCFs. We hypothesize that vertebroplasty will provide a rapid decrease of pain and an early return to daily life activities compared with the control group.Recently, several studies have been published to compare vertebroplasty to conservative treatment of patients with OVCFs, but with different conclusions.22.1This prospective, randomized, clinical trial was registered in Research Registry (researchregistry5624). The conduct of this study followed the Declaration of Helsinki principles and the reporting of this study adhered to the Consolidated Standards of Reporting Trials guidelines for randomized controlled trials. The Institutional Review Board of Yancheng NO.1 People's hospital also approved this study (IRB: YC1002037). Written informed consent was obtained from every participant.2.2Inclusion criteria were age ≥50 years, 1 to 3 vertebral compression fractures, T5 to L5 focal back pain at the level of fracture for up to 6 weeks, score of ≥5 on a VAS, ≥15% loss of vertebral height, and bone edema on magnetic resonance imaging. Exclusion criteria were inability to provide informed consent, chronic back pain requiring opiate use, substantial fracture retropulsion, acute infection, spinal malignancy, neurological complications, and >2 vertebral fractures.2.3Participants were randomly assigned 1:1) to receive either vertebroplasty or control group by the National Health and Medical Research Council Clinical Trials Centre automated telephone service, which provided random computer-generated numbers. The interventional radiologist called this system once the patient was in the procedure room, immediately before the procedure. Randomization was stratified according to age, vertebral height loss, trauma, steroid use, and intervention center. The participants, investigators (other than radiologists doing the procedure), and trial outcome assessors were masked to patient group assignments. To enhance masking, neither the radiologist nor staff at the treating centers had any other role in the trial  was applied from subcutaneous tissue as far as the pedicle entrance. In addition, 1.5 cm2.5The primary outcome was pain relief at 1 month and 1 year, measured with a Visual Analogue Scale (VAS) score ranging from 0 (no pain) to 10 (worst pain ever). We defined clinically significant pain relief as a decrease in VAS score from baseline of ≥3 points. Pain-free days were defined as days with a VAS score of ≤3.The secondary outcomes were Roland-Morris Disability Questionnaire (RDQ), short form (SF-36) score, European Quality of Life-5 Dimensions (EQ-5D), and postoperative complications. The RDQ consisting of 24 questions about dysfunctions in daily activities experienced by patients with back pain. Scores range from 0 to 24, with higher numbers indicating worse physical functioning. SF-36 is a short-form health survey consisting of 36 questions covering 8 dimensions . From the 8 dimensions, 2 summary scores are formed: the Standardized physical component and the standardized mental component. European Quality of Life-5 Dimensions (EQ5D) is an instrument measuring health outcome and consists of 5 dimensions . Each dimension has 3 levels . By combining the scores, 243 different unique health states are possible ranging from perfect health to worst possible health.2.6The sample size was determined for the primary endpoint and was calculated using PASS 2011 software . According to the results of our previous study, the postoperative VAS score for nausea was 2.16 in the control group. We anticipated a difference of 0.72 in the VAS score. With a power of 0.90 and significance level of 0.05, the required sample size was calculated as 70 in each arm. Considering possible exclusion, we decided to include 80 patients in each group.2.7t test, while non-normal variables are examined using Wilcoxon rank sum test. The association between categorical variables is examined using Pearson Chi-squared test or Fisher exact test. All analyses are performed in accordance with intention-to-treat principle.All statistical analyses are performed using SPSS v. 24 . Descriptive statistics of demographic and clinical characteristics are presented with mean standard deviation for continuous scale variables. The difference between normally distributed continuous scale variables is examined using Student 3–16 The aim of this method is to increase the quality of life of the patient by reducing pain, eliminating the need to remain bedridden, and reducing the use of drugs.Osteoporosis and related complications have been increasing with the aging population. OVCFs are the most common among all osteoporotic fractures. OVCFs result in an increase of the incidence of mortality and morbidity, causes back/lumbar pain as well as kyphosis deformity, and reduces the quality of life. Conservative treatment is the initial treatment approach in this type of fracture. It consists of bed rest, analgesic drug use, brace implementation, and physiotherapy. Vertebroplasty was first performed in a painful vertebral hemangioma case in 1984 in France. Its indication has been performed in trauma, osteoporotic fractures, malignant or benign spinal tumors, as well as vertebral osteonecrosis being modified in time. The most common area of usage is currently painful OVCFs. Vertebroplasty technic is a procedure involving the percutaneous injection of cement (polymethylmethacrylate) into the fracture line, with the help of a guide.Three potential limitations to this study were identified. First, VAS pain was recorded by nursing pain assessment records in hospital and thus pain measurements are based on the frequency and accuracy of documentation in the medical record. The second limitation was the small sample size used in this study. Replication of this study on a multi-institutional level would provide less variation between experimental groups and simultaneously increase the reliability and generaliz-ability of the results. Finally, having the same surgeon for all procedures in this study was both an advantage and disadvantage. It is advantageous for consistency and internal validity; however, it may limit the reproducibility of this study.Conceptualization: Dongliang Wang.Data curation: Dongliang Wang, Dingwei Cang.Formal analysis: Dongliang Wang, Dingwei Cang.Funding acquisition: Siqing Wang.Investigation: Dongliang Wang, Dingwei Cang, Ya Wu.Methodology: Dongliang Wang.Resources: Siqing Wang.Software: Dingwei Cang, Ya Wu.Supervision: Siqing Wang.Validation: Ya Wu.Visualization: Ya Wu.Writing – original draft: Dongliang Wang.Writing – review & editing: Ya Wu, Siqing Wang.


Dear Editor,et al. “The Use of Alfa-Lipoic Acid-R (ALA-R) in Patients with Mild-Moderate Carpal Tunnel Syndrome: A Randomised Controlled Open Label Prospective Study”, published in the last issue of Malaysian Orthopaedic Journal1.I have read with interest the article by Passiatore Due to the COVID-19 pandemic, as an hand surgeon, I have to deal with a lockdown of both elective surgery and outpatient.2.Due to legal restriction, in many countries taking charge of elective patients is prohibited or strictly limited, with the fear that many patients feel if requested to come to hospitals, and to the necessity to avoid, as much as possible, non-essential displacements due to the COVID-19 pandemic1. According to my personal experience, ALA-R appears as a very useful tool for management of nervous compression related pain and peripheral neuralgia. Nevertheless, there are many others medications that could be useful in handling typical hand surgery elective pathologies, when surgery has to be delayed or is contraindicated for patient-related reasons4. What should be taken into account, is that different molecules are effective on different aspects of pain and disability. As an example, the Ultra Micronized Palmitoylethanolamide was found to improve the sleep-awake rhythm in these patients, thus giving the way to an improvement in pain perception and overall health conditions5. Other molecules are Group B vitamines and N-Acetyl Carnitine seem to be effectives on neuropathic pain , while Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs), such as glucosamine and chondroitin sulfate, act on nociceptive pain, that is especially related to osteoarthritis6.I have recently reassessed conservative strategies to control or treat musculoskeletal diseases at home, or even just to manage the related-to pain. The above mentioned article focuses on the management of pathologies like carpal tunnel syndromeAs a conclusion, the conservative management for elective surgical pathologies, could find an important place when surgery is not possible or has to be delayed, and can count, nowadays, on a wide range of medications. To get the best result, what appears crucial, is the choice of the good molecule, as not all the pain lays on the same biological base (i.e. nociceptive vs neuropathic) and making the patient aware of the choice and of the expected outcomes, in order to improve his/her compliance to the treatment, what can lead to a better result.