Mechanism-based diagnosis and therapies for chronic pain are lacking. However, bio-psycho-social interventions such as interdisciplinary multimodal rehabilitation programs (IPRPs) have shown to be relatively effective treatments. In this context we aim to investigate the effects of IPRP on the changes in levels of bioactive lipids and telomerase activity in plasma, and if these changes are associated with changes in pain intensity and psychological distress. This exploratory study involves 18 patients with complex chronic pain participating in an IPRP. Self-reports of pain, psychological distress, physical activity, and blood samples were collected before the IPRP and at a six-month follow-up. Levels of arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and telomerase activity were measured. Pain intensity was decreased, and SEA levels were increased at the six-month follow up. A significant correlation existed between changes in SEA levels and pain intensity. AEA levels, were inversely correlated with physical activity. Furthermore, 2-AG and telomerase activity was significantly correlated at the six-month follow-up. This study confirms that IPRP is relatively effective for reduction in chronic pain. Changes in SEA were correlated with changes in pain intensity, which might indicate that SEA changes reflect the pain reduction effects of IPRP. Chronic pain is a frequent and distressing condition, often with a complex origin, that has a significant impact on individuals and society. The prevalence of chronic pain, according to data taken from population surveys, varies widely depending on case definition, and it is estimated 2006) that 19% of people in Europe have experienced pain of a moderate intensity for a duration of at least six months 006 that . Mental Interdisciplinary multimodal rehabilitation programs (IPRPs) are frequently used for the treatment of complex chronic pain. IPRP is a subgroup of interdisciplinary treatments according to the International Association for the Study of Pain (IASP). In Sweden, such biopsychosocial programs are typically based upon cognitive behavioural therapy  and include physical exercise, pain education and return to work strategies. In comparison with usual care programs or “single-modal” approaches, IPRP has been reported with higher efficacy in decreasing pain and disability in chronic pain patients, according to systematic reviews ,7. TheseAlthough IPRPs are the most efficient treatments for chronic pain patients today, there is a lack of mechanism-based approaches for diagnosis and treatment for chronic pain. According to the International Statistical Classification of Diseases and Related Health Problems-Tenth Revision (ICD-10), the diagnosis is based on the duration and anatomical location. Regarding treatment, patients are managed using a trial-and-error approach.Expanded knowledge about ongoing molecular alterations in, e.g., pain/nociceptive, immune and stress systems in chronic pain patients is crucial for the development of mechanism-based diagnosis and treatment. One approach is to study how levels of endogenous molecules—involved in pain/nociception, stress, and immune systems—changes in response to common clinical treatments for chronic pain, e.g., IPRP. Additionally, the associations between clinical variables such as pain and depression with levels of endogenous molecules are important to investigate in chronic pain.An endogenous system associated with multiple biochemical actions affecting, e.g., pain  inflamma1 and CB2). Arachidonoylethanolamide (AEA)  and 2-arachidonoylglycerol (2-AG) are both well-known eCBs. Meanwhile, other ethanolamide lipid mediators, namely the N-acylethanolamines (NAEs), do not activate CB receptors, but partially share metabolic enzymes with eCBs and have other molecular targets. Hence, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) can activate peroxisome proliferator activating receptor-α (PPAR-α) [The endocannabinoids (eCBs)—the lipid mediators of the ECs—are activators of the cannabinoid receptors (CB(PPAR-α) ,14, and (PPAR-α) .The potential role ECs plays in various chronic pain conditions remains to be clarified, but emerging data suggest that this system may play an important role in the body’s descending pain pathways, and preclinical studies support that the eCBs are implicated in the control of pain initiation . FurtherAnother endogenous system associated with stress in humans is the telomer/telomerase complex . Human sThere are several studies that have reported the effectiveness of IPRP as a treatment approach in chronic pain . AlteredHence, the aim of this explorative study is to investigate changes in these two endogenous systems associated with, e.g., pain, stress, and physical activity in patients after participating in an IPRP. Plasma levels of eCBs, and NAEs, as well as TL and TA, were collected from mononuclear cells before IPRP and at six months follow-up in patients with chronic pain, . Within this aim, it is also investigated if levels and changes in these molecules are associated with changes in self-assessed pain intensity, psychological distress (depressive and anxiety symptoms) and physical activity levels, and correlations between levels of the eCBs/NAEs with TL and TA.This prospective study focusses on the longitudinal aspects of IPRP and investigates chronic pain patients before and after IPRP. IPRP was carried out for six weeks. Data of eCBs and NAEs in plasma and TL, TA from lymphocytes/monocytes, self-reports of pain, and depressive/anxiety symptoms and self-assessed physical activity levels were collected before (baseline), immediately after six weeks IPRP, and at a six-month follow-up. We chose to investigate the long-term effects of IPRP more specifically and the results presented in this work therefore focus on data collected before IPRP and at the six-month follow-up.Patients were referred to the Pain and Rehabilitation Centre, University Hospital, Linköping, Sweden by other healthcare services  for complex chronic non-malignant pain conditions. The Pain and Rehabilitation Centre in Linköping is associated with the Swedish Quality Registry for Pain Rehabilitation (SQRP). All clinical departments/centres within specialist care throughout Sweden deliver data to SQRP . The SQRThe study was approved by the Regional Ethics Committee of Stockholm (Dnr: 2014/953-31/1).All patients were given a standard routine clinical examination performed by a physician. The examination consisted of a routine neurological examination, including registrations of systolic and diastolic blood pressures and auscultation of the heart and lungs. The use of medication, including analgesic drugs, was also reported: paracetamol, NSAID, opioids and antidepressants.Medical assessments and decisions to offer IPRP were performed by senior physicians, primarily from specialists in rehabilitation medicine or similar specialties, or by specialists in training under the supervision of a senior colleague. Patients were also assessed by a psychologist, an occupational therapist, and a physiotherapist to be considered for the ability to carry out and complete IPRP. The following general inclusion criteria for IPRP were used: (i) disabling chronic pain (on sick-leave or experiencing major interference in daily life due to chronic pain); (ii) age between 18 and 67 years; (iii) no further medical investigations needed; (iv) written consent to participate and attend IPRP; (v) and agreement not to participate in other parallel treatments. General exclusion criteria included severe psychiatric morbidity, abuse of alcohol and/or drugs, diseases that did not allow physical exercise, or presence of red flags. Red flags are clinical indicators of possible serious underlying conditions requiring further medical intervention.The IPRP was conducted in groups of six to nine patients for six weeks (at least 20 h per week of group-based activities) and was based on CBT (including ACT) in conjunction with physical exercise, pain education, return to work strategies, and pain education . The program also included work-related advice and support, and individually tailored sessions with team members were available if necessary. Individual sessions might also be required for a few weeks following the IPRP. IPRP is mainly a group-based program but with opportunities for individual interventions, based on the clinical picture and the aims of the individual patient. The patient should be motivated and have the potential to make an active change. The individual’s expectations, preparation for changes, and how the pain has affected the possibility of activities were required to be clarified before starting treatment.Numeric rating scale data (0 = no pain and 10 = worst possible pain) were collected for average pain intensity from the previous 7 days.The Hospital Anxiety and Depression Scale (HADS), a short self-assessment questionnaire that measures symptoms of anxiety and depression, comprises seven items in each of the depression (HAD-D) and anxiety (HAD-A) scales . HADS isThe following indicator items, which were developed by the Swedish National Board of Health and Welfare, were used to register physical activity (PA).PA1: During a typical week, how much time do you spend a week on physical exercise that makes you breathless, such as running, exercise gymnastics, or ball sports: 0 = 0–30 min; 1 = 30–60 min; 2 = 60–90 min; 3 = 90–120 min; or 4 = >120 min?PA2: During a typical week, how much time do you spend a week on everyday exercise such as walking, cycling, or gardening: 0 = 0–30 min; 1 = 30–60 min; 2 = 60–90 min; 3 = 90–150 min; 4 = 150–300 min; or 5 = ≥ 300 min?2) was calculated.The weight (kg) and height (m) were measured, and the BMI . Samples were then centrifuged for the removal of red blood cells and the plasma fraction was transferred to new tubes, aliquoted in small portions, and stored at −86 °C. Lymphocytes and monocytes were prepared from the centrifuged citrate-tubes, according to manufacturer’s protocol. Half of the cells were snap-frozen for DNA extraction, and the rest were lysed by incubation with 120 µL CHAPS  including 0.15 units/µL RiboLock  on ice for 30 min, followed by gentle vortexing. Samples were stored at −86 °C.Blood samples were collected in EDTA-tubes and sodium citrate-tubes (BD Vacutainerv/v/v) and mobile phase B containing methanol-acetonitrile (7/3) (v/v) with 0.1% (v/v) formic acid and 1 g/L ammonium acetate in A and B. Gradient elution was applied and started with 100% A during the first 1.5 min, followed by a linear increase towards 100% B, which was achieved after 9 min in total. Between the 11th and 12th min the gradient changed linearly to 100% A, which was maintained for 1 min. An Xbridge C8 analytical column (2.1 mm × 150 mm) with the particle size 2.5 µm obtained from Waters  was used. We used the following selected reaction monitoring (SRM) (m/z) transitions: 348.3/62.4; 326.3/62.4; 300.3/62.4; 328.3/62.4; and 379.3/287.3 for AEA, OEA, PEA, SEA, and 2-AG, respectively. For the corresponding internal standards, we used the following transitions: 352.3/62.4; 330.3/62.4; 304.3/62.4; 331.3/62.4; and 384.3/287.3 for AEA-d4, OEA-d4, PEA-d4, SEA-d3, and 2-AG-d5, respectively. The linearity of the analysis of each analyte was assessed with standard curves ranging from 1 to 25 nM for anandamide and 10 to 500 nM for OEA, PEA, and SEA, and 50 to 1250 nM for 2-AG in duplicate. The linearity of the standard curves was R2 ≥ 0.9 for all analytes. Isotopic dilution was used for quantification of the analytes, performed according to the area ratio of their corresponding deuterated internal standard signal area. Linear regression and X2 weighting were applied. Standards were purchased from Cayman Chemicals . Undetected levels were considered as 0 nM. Xcalibur®  software was used for peak integration and quantification.Levels of lipids were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS) according to a previously published method . Before ® Blood and Tissue Kit  (with some modifications: the speed of centrifuge was changed to 6000× g and incubating was performed at 37 °C for 3 h instead of 56 °C for 10 min). DNA concentration was quantified with NanoDrop ND-1000 Spectrophotometer . Relative TL was determined using real-time quantitative polymerase chain reaction (qPCR) according to [Tel) and the single-copy gene  in triplicate within the same 384-well plate, amplified by using Power SYBR Green in 10 µL total reaction volume. The reaction was performed on QuantStudio 7 Flex  with the following conditions: 50 °C for 2 min, then 95 °C for 10 min, followed by 40 repeats of 95 °C for 15 s and 60 °C for 1 min, followed by a dissociation stage to monitor amplification specificity. The same standard curve of pooled DNA from these patient samples, ranging from 80 ng to 0.128 ng, was run on each plate for both genes and was used to determine the quantity of each gene for each sample. This allowed controlling for differences in the efficiencies between that of Tel and HGB. The gene quantities were then used to determine the T/S ratio for each sample. DNA samples with a Ct standard deviation of ≥0.35 between triplicates or a Ct value outside the standard curve were omitted from the analyses. The correlation coefficients of the standard curves were above 0.99 for each primer set and 384-plate. The inter-plate coefficient of variation (CV) of T/S ratio was 9.1% calculated from a patient sample run in seven 384-well plates. The TL analysis detection success rate was 100%. The primer sequences were (written 5′à3′): Tel1: CGGTTTGTTTGGGTTTGGGTTTGGGTTTGGGTTTGGGTT; Tel2: GGCTTGCCTTACCCTTACCCTTACCCTTACCCTTACCCT; HGB Fw: GCTTCTGACACAACTGTGTTCACTAGC; HGB Rv: CACCAACTTCATCCACGTTCACC. Samples from all three timepoints per person were assayed in the same 384-well plate.Genomic DNA was extracted according to protocol reported by O’Callaghan, N.J. and M. Fenech , using Drding to , where tg for 20 min. The supernatant was transferred to a new tube and total protein concentration was measured using a DC Protein Assay . A volume of each sample containing 3.8 µg of total protein was analysed by PCR using the primers TS (5′-AATCCGTCGAGCAGAGTT-3′) and ACX (5′-GCGCGG(CTTACC)3CTAACC-3′). TSR8, an oligonucleotide with a sequence identical to the TS primer extended with 8 telomeric repeats being AG(GGTTAG), was used to generate a standard curve. The amplification reaction was terminated and 8 µL of the telomeric repeat products were used for the RT-TRAP assay amplified by 8 µL Power SYBR Green in 384-well plates. The analysis was performed on QuantStudio 7 Flex  with the following conditions: 95 °C for 10 min, followed by 36 repeats of 95 °C for 20 s, 52 °C for 30 s and 72 °C for 60 s. All samples and standards were analysed in triplicates.The TA was measured using real-time telomeric repeat amplification protocol (RT-TRAP), using a modified protocol described by Hou et al. . Brieflyt-tests were used for comparison of data between timepoints as the data was shown to be normally distributed using Shapiro–Wilk test. Group mean with standard deviations are presented. Bivariate correlations were analysed using Pearson’s. p ≤ 0.05 was used as level of significance in all statistical analyses. Data analyses were performed using IBM SPSS  and GraphPad Prism .A comparison was made between data from baseline (before IPRP) and six months after IPRP, as the focus of this study was to investigate the long-term effect of IPRP. However, data from baseline and direct after IPRP were analysed and included as a Eighteen patients (13 women and 5 men) with 12 different diagnoses , a mean Pain intensity scorings were significantly decreased from baseline to follow up six months after IPRP. For HAD-A: at baseline, nine patients were rated as non-cases (0–7), two patients as borderline cases (8–10) and seven patients as definitive cases (11–21). At follow-up, the number of non-cases had increased to twelve, borderline cases to three and definitive cases decreased to three. For HAD-D: at baseline, seven patients rated themselves as non-cases (0–7), eight patients as borderline cases (8–10) and three patients as definitive cases (11–21). At follow-up, the number of non-cases had increased to ten, borderline cases had decreased to 4 and definitive cases had increased to four. No statistically significant changes in HAD scores or physical activity levels (PA1 and PA2) were reached on group level six months after IPRP, however a tendence of lower HAD values and higher PA scores could be observed at the six-month follow-up . No signp = 0.04). Concentrations of the lipids before and after the IPRP are presented in Plasma SEA levels were significantly increased at follow up compared to baseline (No significant changes between baseline and follow-up were found for either TL (T/S ratio) (baseline: 1.24 (0.65); follow-up: 1.36 (0.56)) or TA (TPG units/µL) (baseline: 1.49 (1.1); follow-up: 1.47 (0.73)).Correlations between, on the one hand self-reported pain intensity, physical activity, psychological distress, and on the other hand, the lipid mediators , TL and TA were analysed at baseline and at the six-month follow-up. Correlations analyses were also performed on the calculated change (baseline minus follow up = ∆) of these variables . Age andp: 0.05) (p: 0.02). At the follow-up, significant correlations existed between: PA2 and AEA  (p = 0.001). In At baseline, significant correlations existed between: PA1 and AEA   and OEA p: 0.04) , and TA p = 0.05), ∆SEA and ∆TL , and interestingly between ∆AEA and ∆PA (1 and 2)   . (Tablesctively) .SEA levels were significantly increased at the six-month follow-up, and the changes were inversely correlated with changes in pain intensity;AEA and physical activity levels were inversely correlated at baseline and at the follow-up, and moreover, changes in AEA were inversely correlated with changes in physical activity;A strong positive correlation existed between levels of 2-AG and TA at the six-month follow-up.The key findings in this study are as follows:p = 0.05) in patients with complex chronic pain: with a moderate Cohen’s d effect size (0.46). This was in line with a large study from the Swedish Quality Registry for Pain Rehabilitation, which reported small to moderate effect sizes for 22 mandatory outcomes, including pain intensity [p = 0.06)   and can p = 0.11), yet Cohen’s d was 0.59, which may indicate that a substantial increase in aerobic exercise was initiated by the IPRP and that this increase was maintained six months after the program completed.Patients reported higher levels of physical activity at the six-month follow-up compared with pre the IPRP program. PA1  scorings were especially higher at follow-up compared with pre IPRP. However, this increase was not statistically significant (p = 0.04), and moreover, concentration changes in SEA correlated negatively with changes in pain intensity .Concerning the eCB and NAE levels, no significant differences existed except for SEA, which was increased significantly at the six-month follow-up (n = 37) after a 15-week strength training intervention and pain intensity was significantly decreased [Pre-clinical studies have reported SEA with anti-inflammatory, cytokine regulating ,36 charaecreased ; the resecreased  the inteAcute aerobic exercise has consistently been reported to increase AEA in blood in healthy humans ,17,18,38Concerning the strong correlation between 2-AG and TA at the six-month follow-up, to the best of our knowledge this is the first study reporting about this relationship, hence the result needs to be interpreted with caution. However, if this dependence is valid, one possible link could be via corticosteroids. Cortisol has been demonstrated to decrease TA in human T lymphocytes . However2MAX would have increased the validity of the results. Diet has been reported to influence eCBs and NAE’s, as well as TL and TA, and was not controlled for in this study. AEA levels vary during the menstrual cycle and peak in the ovulation phase [The main limitations of this study are the small cohort size (18 patients), the single-armed design, and the heterogeneous patient group. The present biochemistry findings may be common for chronic pain in general but in future larger studies it is necessary to investigate and confirm the results in different diagnoses and mechanisms . Larger studies that include a control group are needed to confirm the validity of our findings. The weakness of self-reported values should also be added here, where multiple factors can play a role in both overestimating and underestimating the level of one’s own physical activity, objective measures, e.g., VOon phase . This waThis study confirms that IPRP relieves pain and may reduce psychological distress in patients with chronic complex pain. When it comes to biochemistry, levels of SEA were increased six months after the program, and baseline to follow-up changes in SEA levels were associated with changes in pain intensity, which may indicate that SEA level changes reflect aspects of the positive pain reduction effects of IPRP. An inverse relationship between self-reports of physical activity levels and AEA levels existed in these patients, and a possible link between the endocannabinoid system and telomerase/telomer complex was detected; however, more studies are needed to confirm the validity of these results.


A progressive reduction in electrodermal activity has been observed comparing the recordings before, during, and after the VR sessions, although these changes were not statistically significant. This brief research report supports the idea that VR could represent a suitable complementary tool for psychological treatment in advanced cancer patients assisted at home.Virtual reality (VR) has been used as a complementary therapy for managing psychological and physical symptoms in cancer patients. In palliative care, the evidence about the use of VR is still inadequate. This study aims to assess the effect of an immersive VR-based intervention conducted at home on anxiety, depression, and pain over 4days and to evaluate the short-term effect of VR sessions on cancer-related symptomatology. Participants were advanced cancer patients assisted at home who were provided with a VR headset for 4days. On days one and four, anxiety and depression were measured by the Hospital Anxiety and Depression Scale (HADS) and pain by the Brief Pain Inventory (BPI). Before and after each VR session, symptoms were collected by the Edmonton Symptom Assessment Scale (ESAS). Participants wore a smart wristband measuring physiological signals associated with pain, anxiety, and depression. Fourteen patients (mean age 47.2±14.2years) were recruited. Anxiety, depression (HADS), and pain (BPI) did not change significantly between days one and four. However, the ESAS items related to pain, depression, anxiety, well-being, and shortness of breath collected immediately after the VR sessions showed a significant improvement ( Cancer significantly interferes in all aspects of daily life, from family and personal relationships to business and financial areas . In addiIn the last years, technological innovation has allowed new solutions to meet old and emerging needs in the healthcare field. One of these is represented by virtual reality (VR), a non-invasive simulation technology that allows the user to be immersed in a multisensory experience. VR technologies can emotionally involve the patients, inducing a positive mood and allowing them to feel like a part of the virtual environment . The disVR has been used as an adjuvant treatment in various clinical conditions to relieve pain, anxiety, and depression , during The evidence about the use of immersive VR in a home-PC program is still insufficient. To fill this gap, the National Tumor Assistance Foundation (ANT), a non-profit organization working in Italy in the field of home-PC and pain management, conducted a pilot study to test the feasibility of VR interventions for cancer patients assisted at home . To the After these encouraging results, ANT introduced the VR headset with interactive and non-interactive contents in its home care practice. Starting from the hypothesis that VR can be used as an effective adjuvant intervention in home-PC to improve anxiety, depression, pain, and other symptoms in advanced cancer patients, this brief report describes the results obtained during the first 18months of this ongoing experience. This pre-post single-arm study aims to reach three objectives:To assess the effect of a VR-based intervention at reducing anxiety, depression, and pain over 4 days;To evaluate the short-term effect of VR sessions on cancer-related symptomatology and physiological signals;To explore whether the two contents  can have a different effect on the cancer-related symptomatology.Participants were advanced cancer patients assisted within the home-PC program of ANT Foundation in the metropolitan area of Bologna . We excluded patients who were under 18 and over 70, with visual and hearing impairment, unable to understand the informed consent, to answer the questionnaires due to cognitive impairment, to understand the Italian language, with a diagnosis of epilepsy, dementia, or other neurological disorders, brain cancer or brain metastases, or heart attack in the last year. Each participant signed written informed consent for intervention and data collection before starting the study. Data collection lasted from May 2019 to July 2020. To verify the patients’ eligibility, ANT psychologists discussed with the ANT physician, evaluating whether the patient respected all inclusion criteria. After that, the psychologists contacted the patient to propose and explain the study design.We collected data on gender, civil status, cohabitation, occupation, education, and confidence with technology by a questionnaire. Cancer diagnosis, Karnofsky Performance Score KPS; , extensiThe validated Italian version of Brief Pain Inventory BPI;  is an eaWe used a smart wearable wristband in order to evaluate the psychophysiological effects of the VR, as also reported in other studies . We seleThis study has been designed as a pre-post single-arm study. The intervention was based on the supply of a VR headset with customized contents. The headset was Mirage Solo VR (LENOVO S.r.l.) – including a remote controller – supplied at the home of the participant for 4days.The ANT psychologist suggested using the headset in moments of psychophysical discomfort . We did not set a minimum or a maximum on usage time nor on the number of sessions, in order to not force the use of the VR headset. Participants were also instructed to take off the VR headset immediately if they had any side effect and to promptly inform the investigator for having support. Possible side effects reported in the VR headset user manual  are dizzThe VR headset was provided with both interactive and non-interactive contents specifically developed for ANT patients by , and the BPI (Patients received the VR headset and kept it at home for 4days. On the first day (T0), an ANT psychologist described the study to participants, who then signed the informed consent form. The psychologist asked them to answer the socio-demographic form, the HADS , and the the BPI . The cli the BPI  directly the BPI  to recorAfter checking the non-normality with a Kolmogorov-Smirnov test, changes in anxiety, depression (HADS), and pain (BPI) between T0 and T1 were investigated with a Wilcoxon signed-rank test. To evaluate the short-term effects of VR on ESAS items and physiological signals, we used linear mixed effect models . The most common primary site of the tumor was the gastrointestinal tract (28.6%); seven patients (50.0%) suffered from localized cancer, and seven patients (50.0%) suffered from metastatic cancer. Five participants (35.7%) did not assume drugs, one participant (7.1%) took pain medication together with antidepressants, one participant (7.1%) took pain medication together with anxiolytics and antidepressants, and seven participants (50.0%) took only pain medication .No negative side effect during or after the use of VR was reported.A total of 805h and 31min of physiological signals were collected during the 4-day observation period. During the VR sessions, 10h and 39min were recorded, during which EDA and IBI signals were classified as high quality for 88% and 36% of the time, respectively see . SupplemA total of 73 VR sessions from 14 participants were collected . The totThe results of the T0-T1 and immediate effects of VR are shown in Anxiety, depression (HADS), and pain (BPI) levels did not change significantly between T0 and T1.The nine LMMs of the ESAS items showed a significant improvement in pain, depression, anxiety, well-being, and shortness of breath immediately after using the VR. The four LMMs of the physiological parameters  showed no significant changes before, during, and after the VR sessions. Albeit not statistically significant, the EDA showed a progressive decrease during the three phases, while the HR, SKT, and AI had a reduction during the VR sessions compared to the 10-min time windows before and after the intervention.r=0.63, p<0.05). On the other hand, from the correlation analysis between usage time of the single VR session and post-pre differences in ESAS scores, we found significant negative correlations for anxiety , worst feeling of well-being , and shortness of breath .From the correlation analysis between total usage time for each participant and post-pre differences in HADS and BPI scores, we found a significant positive correlation for the “mean pain” BPI item , anxiety, or depression (HADS) over a four-day period. Nonetheless, VR sessions showed an immediate effect in relieving patient-reported symptomatology (ESAS), and no significant change in physiological parameters  could be appreciated. No differential effect was found between interactive and non-interactive VR contents. To our knowledge, this research and the previous pilot study  are amonIn this setting, the VR intervention was appreciated by participants, and no one reported adverse side effects caused by its use. In agreement with these results, several studies confirmed user satisfaction, comfort, and feasibility of VR-based psychological interventions on patients with severe medical conditions , in PC pAs a further step, this pre-post study assessed the degree of voluntary use of the VR headset at home over multiple days. All patients used at least once the VR device during the intervention, though the VR usage time, and the number of sessions decreased over the days. This could be due to the reduction in “the element of surprise” given by the novelty of the VR experience. Therefore, the inclusion of a variety of multimedia contents could be crucial to maintain the patients involved in the VR treatment for a longer period. To encourage an increased use of the device, ANT Foundation is working to implement new and more enjoyable VR contents.In the pilot study, The absence of long-term effects assessed by HADS and BPI could be also due to other factors. For instance, as shown by The analysis of ESAS immediately before and after each VR session showed a significant reduction in pain, depression, anxiety, shortness of breath, and an improved well-being. These findings are in agreement with those of Niki and colleagues, demonstrating that a one-time VR intervention is sufficient to significantly reduce pain, tiredness, drowsiness, shortness of breath, depression, and anxiety measured by ESAS in a group of terminal cancer patients . AnotherRelevant insights on short-term effects can also be derived from physiological signals. Such these signals have already been used in clinical research to assess the subjects’ arousal in response to different events. Moreover, physiological signals are often employed as a complementary tool in oncological pain assessment . The proWe investigated whether the usage time could be related to an improvement in cancer-related symptomatology. For the long-term effects , we found a significant positive correlation with the “mean pain” BPI item. Since participants were asked to use the VR headset in moments of psychophysical discomfort, this positive correlation could mean that those patients with a worsening of pain used more the VR headset. On the other hand, for the short-term effects , we found significant negative correlations between usage time of the single VR session, anxiety, and other related symptoms . This could represent an effective improvement provided by a longer VR usage time.No differential effect was found between interactive and non-interactive VR contents. Since interactive contents require more attentive resources, they are expected to have a more substantial distractive effect  and, in This study presents some limitations. According to the aims and the design of the study, patients were instructed to freely use the VR headset at home. This can introduce many factors that cannot be controlled, such as the number of VR usages and the context in which the patient used the VR. Other equally important aspects are the small sample size and the absence of a control group. Eventually, there may be several confounding effects. For example, patients who feel worse could use more VR. This can influence the results and cannot be corrected due to the lack of a control group. All these factors limit the strength of the conclusion drawn about whether any effects of the intervention can be ascribed solely to the VR. Despite these limitations, this is a study on a real-world population based on a daily home care practice. We tested the use of VR in real-world condition, and from this pre-post study, we were able to detect interesting aspects about the use of the VR in home palliative care settings that will be deepened in a next randomized controlled trial.This brief research report supports that immersive audiovisual technology, such as VR, could represent a suitable tool to integrate the standard psychological support for patients with advanced cancer to improve their well-being with an immediate effect on their symptomatology. For the first time, this intervention brought the VR device to the PC patients’ homes. The participants could benefit from this technology freely and use it in moments of worst psychophysical discomfort. Indeed, this approach is highly innovative, and it is worthy of deeper investigations in combination with other distraction and/or relaxation techniques in future larger-scale studies.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 the Ethical Committee of Area Vasta Emilia Centro . The patients/participants provided their written informed consent to participate in this study.SM: conceptualization, investigation, methodology, data analysis, and writing original draft. VS: conceptualization, investigation, methodology, data collection, and writing original draft. AG: investigation, data collection, and writing original draft. PP: methodology, data analysis, and writing review and editing. RO: supervision, project administration, and writing review and editing. SV: conceptualization, supervision, and project administration. RP: supervision and project administration. LC: conceptualization, supervision, and project administration. 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Acute pain in neurosurgical patients is an important issue. Opioids are the most used for pain treatment in the neurosurgical ICU. Potential side effects of opioid use such as oversedation, respiratory depression, hypercapnia, worsening intracranial pressure, nausea, and vomiting may be problems and could interfere with neurologic assessment. Consequently, reducing opioids and use of non-opioid analgesics and adjuvants , as well as non-pharmacological therapies were introduced as a part of a multimodal regimen. Local and regional anesthesia is effective in opioid reduction during the early postoperative period. Among non-opioid agents, acetaminophen and non-steroidal anti-inflammatory drugs are used frequently. Adverse events associated with opioid use in neurosurgical patients are discussed. Larger controlled studies are needed to find optimal pain management tailored to neurologically impaired neurosurgical patients. Acute pain following acute brain injury could be substantial, but commonly it is not the primary consideration of the neurosurgical intensive care (NSICU) patients. The main reason for this is a priority of preventing secondary brain damage after trauma or surgical procedure , 2. PresSeveral ERAS protocols (enhanced recovery after surgery) were recently developed for postoperative patients and perioperative pain treatment is included in them . ReducedIn this review, we will present the pain assessment and the most common modalities of analgesia in NSICU patients. We will discuss the problems associated with analgesia in patients with impaired consciousness, and complications of opioid use in patients with acute brain injury. Respiratory depression, gastrointestinal dysmotility, delirium, and addiction with possibilities to reduce them will be highlighted.Acute pain after craniotomy is considered moderate to severe during the first two postoperative days. It is often underrated and hard to estimate, potentially becoming chronic , 9. No aThe introduction of the ERAS protocol in neurosurgery aims to accelerate postoperative recovery and length of stay in the ICU, and analgesia with fewer opioids in the early post-craniotomy period is crucial in achieving these goals. By adhering to these protocols, Elayat and co-workers reduced the length of stay in the ICU, reduced the number of episodes with VAS >4, and reduced opioid consumption in the patients undergoing elective craniotomy for supratentorial neurosurgery . ConsequLocal and regional anesthesia techniques, such as local scalp infiltration/block seem to be effective in the early postoperative period . PostopeAmong non-opioid agents, acetaminophen and non-steroidal anti-inflammatory drugs are used most frequently in the first postoperative days to reduce the dose of opioids , 14. RecAnalgesia in NSICU patients with acute brain injury must not be a simple extension of post-craniotomy analgesia.Pain treatment in patients who have altered mental status before and after craniotomy is challenging. In NSICU patients, pain may be postoperative, e.g., after a craniotomy. It can be caused by intubation, mechanical ventilation, insufficient mobilization, as well as placement of nasogastric tube, urinary catheter, or central venous catheter. Several factors including sepsis, use of vasopressors, multiple comorbidities, previous , or new There are several tools adopted for the pain assessment in mechanically ventilated ICU patients, and patients with altered mental status. Behavioral Pain Scale (BPS), Critical Care Pain Observation Tool (CPOT) , or NociSevergnini et coworkers compared CPOT and BPS to examine their applicability in awake and sedated patients. They confirmed that both scales correlate with pain. In the comparison, CPOT was more sensitive , and BPS was found to be more specific  for pain assessment. The best results were obtained by combining both scales . In anotCurrently, none of the above rating scales can be considered the gold standard for pain assessment in neurocritical patients. As with other ICU patients, pain should be routinely assessed using validated behavioral scales and documented, especially before invasive procedures and physical therapy .Implementation of standardized pain assessment protocols for the NSICU patients is important, but the actual implementation and adherence to these protocols remains an area for improvement and further investigations. Vital signs should not be used as a sole measurement, and surrogates for pain assessment . Using tThe implementation of clinical assessment tools may lead to reduced use of analgesic and sedative agents, as observed in the nurses' study carried by Gelinas and coworkers . In the The situation is more complicated when patients' condition dictates prolonged sedation, mechanical ventilation, and when other invasive and painful procedures are routinely performed in NSICU. In such situations, a protocol called “analgesia first sedation” may be useful by increasing compliance with the ventilator but may lead to increased opioid use . In neurIn patients with acute brain injury, intracranial pressure oscillations are associated with hemodynamic instability and are treated with a reduction in intracranial pressure by continuous use of sedatives, such as propofol and opiates. Sedatives and opioids are given commonly, based on the blood pressure and pulse values to maintain smooth circulation and mechanical ventilation . DiffereParoxysmal sympathetic hyperactivity (PSH) is a syndrome resulting usually from traumatic brain injury (79.4% of the patients), and rarely from hypoxia (9.7%) or cerebrovascular accident (5.4%) . Since tCommon problems with PSH are difficult mechanical ventilation, difficult maintenance of fluid and electrolyte balance, management of increased body temperature, increased number of blood specimens, and unresponsiveness of the symptoms to treatment.One of the treatment goals in brain-injured patients is symptoms prevention and reduction . The symCurrently, dexmedetomidine and gabapentin are used for both symptom and opioid reduction. In a recent study, Peng and coworkers have confirmed that dexmedetomidine reduces paroxysmal hypertension, average time for normalization of body temperature, heart rate, and respiratory rate below 25 breaths per minute, but does not protect against the recurrence of PSH . In the Gabapentin is a promising drug for the treatment of PSH. Godo and colleagues reported a case series of patients who were resistant to benzodiazepines, opioids, and non-steroidal anti-inflammatory drugs. Initial gabapentin doses of 200 mg 3 times a day increased to 400 mg 3 times a day resulted in a reduction of PSH symptoms . To achiAlthough some preclinical studies have suggested that opioid receptor agonists may be beneficial in brain injury, capable of reducing brain edema as well as of providing neuroprotection during a stroke , these pRespiratory depression with consequent hypoxia and permanent brain injury has often been described after acute opioid intoxication . The outGastrointestinal dysmotility, i.e., gastroparesis and bowel paralysis are commonly observed in the acute phase of injury in neurosurgical patients , 46. BotKieninger and coworkers studied a promotility protocol in adult NSICU patients with acute severe brain injury and anticipated mechanical ventilation for more than 3 days . All patper se, may influence gut dysfunction via unknown mechanisms. Larger prospective studies are needed to answer the true OIC incidence and optimal treatment in NSICU patients with brain injury.Schmittner and coworkers reported no difference in the time period until full enteral nutrition or first defecation between patients receiving opioid fentanyl and S(+)-ketamine in neurosurgical patients . This suA decrease in the mean arterial blood pressure is well-known during fentanyl, remifentanil, or alfentanil administration , as wellAddicted patients are a growing category in ICU. Analyzing toxicological samples taken from 44 patients admitted to the Intensive Care Unit Ruiz-García and coworkers confirmed the use of ≥1 substance in 74% of patients. The most consumed substances were alcohol and tobacco (> 55%), and cannabis, amphetamines (> 11%), and cocaine (9%). Discontinuation of each of these substances can lead to withdrawal syndrome .Opioid addiction is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors. Usually, they need a special approach while on opioid maintenance treatment during the ICU stay, since the opioid restriction is not recommended during the acute illness . The toxWithdrawal syndrome may be a serious complication during ICU treatment . The mosIn NSICU where opioids are commonly used, withdrawal may be difficult to recognize. Its recognition could be even poorer because no valid tools were developed for ICU patients. Opioid withdrawal syndrome may mimic PSH or other manifestations of brain damage . Opioid Promoting non-opioid analgesics and reducing opioid use is important to minimize the use of opioids in previously opioid-naïve patients after discharge from the NSICU. To date, there are no studies to confirm the frequency of opioid use in neurosurgical patients after discharge from the ICU. Data from other fields of intensive care confirm that this proportion is significant. Based on the recent cohort studies 40.8% (346 in 848) medical ICU patients and 45%  opiate-naïve patients were discharged with a new opioid prescription , 68. A sIn clinical situations where opioid use cannot be avoided, nor can opioids be replaced by other drugs, opioid rotation may be useful. It can reduce both risks of opioid dependence and of opioid tolerance, i.e., increase the opioid dose to maintain equianalgesic effects , 69.Patients may develop delirium as a consequence of opioid administration in the ICU. Pisani and coworkers reported patients who received opioids had a longer duration of delirium . The incin vivo study tramadol was able to minimize perivascular edema, neuronal necrosis, inflammatory cell infiltration in acute and chronic ischemia/reperfusion injury (in vitro and in vivo studies. Possible mechanisms are signaling pathways for inflammatory response, oxidative stress, neurotransmitter regulation, mitochondrial function, apoptotic pathway, and autophagy (There are numerous unresolved questions in the field of analgesic use in acute brain injury, such as whether the choice of analgesics may influence neurological recovery in acute brain injury. In the n injury . The comutophagy . This efutophagy . While dutophagy . There aBoth pain assessment and pain control are challenging in neurosurgical patients with altered consciousness. Opioid use is common in NSICU but can lead to respiratory depression and difficult neurological evaluation from oversedation. Avoiding opioids and the use of alternative medications and therapies are recommended. Multimodal postoperative analgesia and proper drug selection in the ICU may reduce the side effects of opioid treatment. Further studies should confirm whether the choice of analgesia and opioid restriction in patients with severe brain injury may influence outcomes.SS and SK each wrote sections of the paper and performed the literature review. SK and NK have prepared tables for publication. SK, NK, and SS have approved a final version of the manuscript. All authors contributed to the article and approved the submitted version.This manuscript was supported by IP16-20 and IP1-21 by J.J. Strossmayer University, Medical Faculty, Osijek, Croatia.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To describe a case series of combined Boston Type 1 Keratoprosthesis with pars plana vitrectomy, silicone oil placement, and fluocinolone acetonide intravitreal 0.59 mg implant (RETISERT®), and report its safety and efficacy in preventing phthisis bulbi in patients with uveitis-associated hypotony and concurrent corneal edema.A retrospective review of patients with chronic uveitis, corneal decompensation and concurrent hypotony who underwent the combined approach described here between 2015 and 2020 was conducted. Three patients were treated using the combined approach. Post-operative recovery was unremarkable in all cases and the patients’ corneal condition remained stable on follow up. No patient developed phthisis, retroprosthetic membrane, or infectious endophthalmitis. Average intraocular pressure one year after intervention was 2.7 to 6.4 mmHg higher compared to a year prior.The approach described is potentially safe and effective in preventing phthisis and membrane formation in uveitis-associated hypotony and keratopathy. Hypotony associated with uveitis is an end-stage manifestation of severe ocular inflammation and is associated with loss of visual acuity. It emerges when aqueous production by the ciliary body does not match the outflow , and canLong standing hypotony may also cause corneal endothelial pump dysfunction and stromal edema . While tThe intravitreal 0.59 mg fluocinolone implant , is a well described treatment for uveitis, providing excellent control of inflammation for 24 to 30 months after implantation . It exer.The purpose of this study is to report the authors’ experience in treating corneal edema in the setting of uveitis-associated hypotony with combined Boston Type 1 Keratoprosthesis placement , silicone oil injection, and 0.59 mg fluocinolone acetonide intravitreal implantThis is a retrospective study of patients with hypotony who underwent fluocinolone acetonide implantation and single-stage keratoprosthesis with silicone oil injection between 2015 and 2020. Patients with chronic uveitis who had evidence of corneal decompensation with concurrent hypotony were included, and their electronic health records were reviewed.All patients underwent surgery for an indication of corneal edema in the setting of uveitis and hypotony, and all patients elected to undergo fluocinolone acetonide implantation for uveitis control. All patients underwent 23-gauge pars plana vitrectomy with silicone oil injection (5000 cSt). One patient had a pre-existing retinal detachment. Intraocular pressures after keratoprosthesis placement were estimated by scleral pressure and were measured using pneumatonometry in the inferotemporal quadrant to compare with corneal pressure measurements prior to keratoprosthesis placement .A 47-year-old woman with a history of chronic unilateral non-granulomatous anterior uveitis with cystoid macular edema (CME) of the left eye presented with eye pain for surgical visual rehabilitation evaluation Table . Her hisA 53-year-old woman with bilateral steroid response glaucoma and chronic panuveitis presented for surgical treatment of corneal edema and hypotony Table . Her lefA 57-year-old man with a history of bilateral immune reconstitution panuveitis secondary to CMV retinitis in the setting of human immunodeficiency virus (HIV) developed significant hypotony in the right eye requiring repeat injections of hyaluronic acid Table . The lefHe has been maintained without bandage contact lens placement, as achieving an appropriate fit was difficult. The ocular surface was stable, and he did not have a retroprosthetic membrane for 5 years after surgery. However, he developed a small epithelial defect at 5 years that responded within 1 week to amniotic membrane placement.n = 2) and 6.7 mmHg (n = 3), respectively, average IOP before and after silicone oil placement with keratoprosthesis was 4 mmHg (n = 1) and 10 mmHg (n = 3). These findings suggest that combined keratoprosthesis insertion and silicone oil placement may help maintain higher IOP when compared to silicone oil alone, thus lowering the probability of hypotony maculopathy.Hypotony may lead into several irreversible, vision-impairing complications in the posterior segment. The resulting shrinkage and collapse of the scleral wall due to low intraocular pressure (IOP) is thought to fold and wrinkle the chorio-retina, particularly in the peri-foveal region, distorting neurosensory elements with permanent visual loss . AdditioIn phthisical eyes, the corneal epithelium is often normal, and the ensuing edema is stromal due to endothelial decompensation . This haRetroprosthetic membrane formation is a common occurrence after keratoprosthesis surgery . In a prAll eyes in this study also had stable ocular surfaces without the need for a bandage contact lens. The patients in this study had difficulty getting a lens fit owing to the abnormal contour of their ocular surface in the setting of a pre-phthisical state prior to keratoprosthesis placement. Even extremely flat, large diameter lenses were unable to be retained successfully. Despite this, these patients did not experience epithelial breakdown and keratolysis. Stability of the ocular surface in the setting of silicone oil and keratoprosthesis placement to treat hypotony has previously been noted , 21. We This study has several strengths, including unremarkable post-operative recovery and absence of any complications, particularly retroprosthetic membrane formation, infectious endophthalmitis and sterile keratolysis in uveitis-associated hypotony and keratopathy. While inferotemporal scleral pneumatonometry is a promising method for measuring IOP in those with keratoprosthesis, this has not been validated in eyes with hypotony . Future Combined treatment of uveitis-associated hypotony and keratopathy with Boston Type 1 Keratoprosthesis, silicone oil placement, and fluocinolone acetonide implant may be a safe and effective method to prevent phthisis.


ABSTRACT IMPACT: The importance of this study is to evaluate the responses following the exposure of opioid drugs in young adults to address the current opioid epidemics OBJECTIVES/GOALS: To compare the proportion of patients between 18 and 25 years of age, who develop an opioid abuse disorder following dental surgery, to those following other surgical procedures, when an opioid drug is used for acute postoperative pain control. METHODS/STUDY POPULATION: We fashioned an IRB-sponsored retrospective cohort study of patients, ages 18 to 25 years old, who presented for dental surgery or other medical surgical procedures, at Strong Memorial Hospital Medical Center, at the University of Rochester and received opioid drug treatments, for acute surgical pain management. Patients with the diagnosis of acute surgical pain were included in the study. However, those with chronic pain or other related abnormalities were excluded, even if a diagnosis of acute surgical pain was present in the electronic chart. The clinical data were retrieved from electronic medical records and NYS-iStop records. All statistics were significant at the level of <0.1 RESULTS/ANTICIPATED RESULTS: We identified 167 subjects, of whom, only 150 subjects met inclusion criteria (n=100) in dentistry and (n=50) in other medical specialties. Patients were followed up in a 7-year period. Most of the subjects were females (n=91), Caucasian (n=80), and lived in a suburban location (n=78). The most frequently prescribed opioid included hydrocodone (n=119). A significantly higher proportion (8.7%) of patients developed opioid abuse disorders in the control group, compared to 1% of subjects in the experimental group (p 0.02). Those in the control group received marginally significant higher doses of MMEs 447.2 +/-644.8 mg vs 306.2 +/-354.7mg in the experimental group (p 0.086). Those in the control group had significantly longer periods of opioid treatment 10 (+/-12) compared to 6(+/-6) days in the experimental group DISCUSSION/SIGNIFICANCE OF FINDINGS: It is paramount to evaluate the morphine milligram equivalents, and duration of opioid treatment given to the young population with acute surgical pain, to prevent opioid abuse disorders in this vulnerable cohort.


In the 11/27 patients with LoC, SCS efficacy on pain intensity (36.89%) was accompanied via paresthesia coverage recovery (55.57%) and pain surface decrease (47.01%). At 12-month follow-up, 81.3% preferred to keep tonic stimulation in their waveform portfolio. SCS conversion using adapters appears promising as a salvage solution, with an emphasis on paresthesia recapturing enabled via spatial retargeting. In light of these results, adapters could be integrated in SCS rescue algorithms or should be considered in SCS rescue.While paresthesia-based Spinal Cord Stimulation (SCS) has been proven effective as treatment for chronic neuropathic pain, its initial benefits may lead to the development of “Failed SCS Syndrome’ (FSCSS) defined as decrease over time related to Loss of Efficacy (LoE) with or without Loss of Coverage (LoC). Development of technologies associating new paresthesia-free stimulation waveforms and implanted pulse generator adapters provide opportunities to manage patients with LoE. The main goal of our study was to investigate salvage procedures, through neurostimulation adapters, in patients already implanted with SCS and experiencing LoE. We retrospectively analyzed a cohort of patients who were offered new SCS programs/waveforms through an implanted adapter between 2018 and 2021. Patients were evaluated before and at 1-, 3-, 6- and 12-month follow-ups. Outcomes included pain intensity rating with a Visual Analog Scale (VAS), pain/coverage mappings and stimulation preferences. Last follow-up evaluations (N = 27) showed significant improvement in VAS ( Paresthesia-based Spinal Cord Stimulation (SCS) is a well-established therapy with robust clinical evidence aimed at treating patients suffering from refractory Failed Back Surgery Syndrome(FBSS)/Persistent Spinal Pain Syndrome after surgery PSPS-T2) ,2,3,4. I ,2,3,4. LoE may happen over time for various reasons ,10 and cCurrently, EC-marked (European Conformity) adapters can be used for patients implanted with an SCS device, enabling clinicians to upgrade the Internal Pulse Generator (IPG) with a different stimulation technology, without changing the existing lead(s). With a simple surgical procedure, previously inaccessible SCS programs and waveforms can be used to regain pain relief ,17. PropWe designed a retrospective study to further investigate the potential benefit of new spatial and temporal SCS paradigms proposed to patients for whom SCS has shown LoE. Patients previously implanted with an SCS system, which no longer provides adequate pain relief , were implanted and assessed with a 12-month follow-up period to confirm and to further characterize the outcomes of therapy conversions. In addition, our team created a 3D-computerized triple-patented pain mapping tool , to be aA retrospective monocentric, observational, longitudinal, real-life cohort study including all consecutive patients, in whom an adapter had been implanted in our department  was conducted between 2018 and 2021. Written informed consent was obtained from all patients included in the study before data collection. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the Poitiers University Hospital (N° F20210507150101). The study did not receive any financial support from industry and industry did not participate in data collection or in data analysis.Patients meeting the following criteria were included in the study: presents refractory neuropathic chronic pain ; had been implanted with a previous SCS system and had demonstrated significant pain relief following their lead trial and remained postoperatively satisfied with the stimulation for months or years; had experienced LoE over time and were finally considered as FSCSS patients, despite SCS initial success; evaluated by a multidisciplinary team in order to exclude psychological  and financial  reasons that might explain SCS loss of efficacy and to rule out hardware dysfunctions; were eligible for an SCS adapter implantation.Two groups of patients were identified:− The “loss of coverage” group (LoC group) including patients for whom pain coverage was not adequate (<60%).− The “SCS tolerance” group (SCStol group), including patients with adequate pain coverage for whom SCS no longer provided pain relief.Prior to considering an adapter implantation, patients previously implanted with an SCS device and still presenting with refractory chronic neuropathic pain due to LoE had to be reassessed in a multidisciplinary pain clinic to (i) identify the potential cause of LoE, (ii) rule out any hardware dysfunction and (iii) investigate any reprogramming issues or lead impedance. Furthermore, the absence of lead displacement was systematically assessed using recent imaging data, especially in the case of loss of coverage. In the case of a negative issue managing persistent pain, patients were proposed to be implanted with an adapter (Boston Scientific VerciseTM M8 Adapter or PrecisionTM S8 adapter). An externalized temporary generator was implanted for a seven-day SCS screening trial period. The adapter screening test was considered as positive if the patient achieved a global pain VAS score decrease ≥50% after a seven-day period trial according to the French Health Authority guidelines or if the improvement was clinically important according to patient goals and expectations and was permanently implanted with a new SCS device at the end of the SCS adapter screening trial. Patients who did not achieve 50% pain reduction or clinically important improvement were proposed to either get their previous SCS device reconnected or completely explanted (lead(s) was either explanted or not, based on patient preference).All patients receiving an adapter IPG were upgraded with the same technology  enabling spatial and temporal re-targeting, using various reprogramming strategies: the shape of the electrical field could be adapted using Multiple Independent Current Control (MICCTM) technology to optimize spatial targeting , and onePatients were assessed at baseline (before adapter implantation), and at 1, 3, 6 and 12 months of follow-up. During these visits, patients reported the efficacy of their stimulation and change waveforms if needed. During the programming sessions of the visits, new waveforms, combined or not, were randomly proposed to the patient. The patient reported verbally if the stimulation was able to cover his/her painful area and finally chose the program he/she preferred. Programming sessions lasted about 45 min.Pain intensity was assessed using a global Visual Analogic Scale (VAS), functional disability using the Oswestry Disability Index (ODI), health-related quality of life using the EuroQuol-5 Dimensions 5 Levels (EQ-5D-5L) questionnaire, depression and anxiety levels using the Hospital Anxiety and Depression Scale (HADS), and patient satisfaction using the Patient Global Impression of Change (PGIC), which measures the patient’s belief about the efficacy of treatment . Pain surface area and paresthesia coverage were collected from a touch screen, where the patient drew the various pain and paresthesia areas, which were then represented in maps and diagrams. The pixels of the patient’s drawing were then converted to cm², using several anatomical landmarks, patient morphology and morphometry, to optimally and accurately measure the pain area, using a patented data processing system  . The paiR software  was used for the statistical analysis.Quantitative variables were described using mean and its standard deviation (SD) and qualitative variables were described using the number of patients and their percentage in each modality.t-test or a Wilcoxon signed-rank test, depending on the normality of distributions. Normality of distributions was tested using the Shapiro–Wilk test. The confounding factors age, sex and time between the previous SCS system implantation and the adapter implantation were tested and were not statistically clinically significant. For this reason, and to improve interpretability, we have chosen not to include the confounder factors in this study to improve interpretability [The significance of global change of each of the study outcomes  following implantation of an adapter was evaluated by applying a mixed effect regression model with the follow-up visit  as a fixed effect variable and a random patient-specific intercept to account for within-patient dependencies. When the follow-up effect was significant, each follow-up visit was compared to baseline using a paired tability .Three approaches were used to treat missing data. The first analysis consisted of using only available cases for each follow-up. This approach might lead to biased results . Therefore, a second analysis was carried out using data from the last available observation of the patient for the remaining follow-up visits (last observation carried forward method). The seven-day screening trial outcome was considered as the last observation for patients with a negative screening trial. The third approach is a worst-case analysis ,27. In tt-test or a Mann–Whitney test depending on the normality of distributions. An exact Fisher test was used to compare qualitative variables between the two groups.We also compared baseline characteristics, percentage of pain surface decrease, paresthesia coverage and percentage of pain intensity decrease between the LoC group and the SCStol group for each follow-up visit . For quantitative variables, these comparisons were conducted using a p-value of less than 0.05 was considered as statistically significant. As recommended by Rothman et al. [p-value adjustment for multiple comparisons was considered in this exploratory study with preplanned outcomes and analysis.All tests were conducted as two-tailed. A n et al.  and Althn et al. , no p-vaBaseline characteristics of the patients and the study follow-up are presented in Results of paired comparisons for 1-month, 3-month, 6-month and 12-month follow-ups are presented in p < 0.0001). The VAS significantly decreased from baseline to 1-month , 3-month , 6-month  and 12-month follow-up   .p = 0.0001). A significant decrease in ODI was also observed from baseline to 1-month , 3-month  and 6-month follow-up . The decrease did not persist at 12-month follow-up .For the ODI score, the mixed effects model showed a significant time effect (p < 0.0001). The EQ-5D index increased significantly from baseline to 1-month , 3-month  and 6-month  but not at 12-month follow-up .For the EQ5D index, the mixed effects model showed a significant time effect (p = 0.012). The HADS depression score also improved significantly from baseline to 1-month , 3-month  and 6-month follow-up  but not 12-month follow-up .For the HADS depression score, the mixed effects model showed a significant time effect (p = 0.002). The HADS anxiety score improved significantly from baseline to 1-month follow-up  but not at 3-month , 6-month  and 12-month follow-up .For the HADS anxiety score, the mixed effects model showed a significant time effect (p = 0.006). The total pain surface significantly decreased from baseline to 1-month , 3-month  and 12-month follow-up , but not 6-month follow-up .For the total pain surface, the mixed effects model showed a significant time effect (p = 0.003). The very intense pain surface significantly decreased from baseline to 1-month , 3-month , 6-month  and 12-month follow-up .For the “very intense” pain surface, the mixed effects model showed a significant time effect (n = 3), were explanted due to an infection (n = 1) and patients for whom no follow-up was available (n = 2).In this analysis, we considered the last follow-up available for each patient. Seven-day screening trial data was considered as the last follow-up for patients who had a negative screening trial (p = 0.0001), the ODI score , the EQ-5D-5L index , the HADS anxiety score  and the pain surface . However, the HADS depression score did not change significantly between baseline and the last follow-up .Differences for global VAS, ODI score, EQ-5D index, HADS depression and anxiety scores and pain surface between baseline and the last follow-up are presented in In this analysis, patients with missing data were considered as non-responders and baseline data were used to impute the missing follow-up data for each patient.p = 0.0011), 3 months , 6 months  and 12 months . The ODI score significantly improved from baseline (48.5 ± 15.9%) to 1 month , 3 months  and 6 months , but did not significantly differ after 12 months . The EQ-5D-5L index significantly improved from baseline (0.25 ± 0.2) to 1 month , 3 months  and 6 months , but was not significantly different after 12 months . The HADS depression score significantly improved from baseline (6.2 ± 3.7) to 1 month , 3 months  and 6 months , but was not significantly different after 12 months . The pain surface significantly decreased from baseline (1085.2 ± 1360.7 cm²) to 1 month , 3 months  and 12 months , but was not significantly different after 6 months .Worst-case analysis showed a significant improvement of the global VAS from baseline (75.1 ± 14.9 mm) to 1 month  and the SCStol group (n = 16). p = 0.034) and at 3 months . The patients in the LoC group had significantly better paresthesia coverage at 1-month follow-up than the SCStol group (p = 0.048). We did not find any other significant difference in the analysis in the percentage of VAS decrease at all follow-ups and for the percentage of pain surface and paresthesia coverage at 6- and 12-month follow-ups.In this analysis, we compared the pain relief, pain surface decrease and paresthesia coverage between the LoC group (n = 10), 6 patients (60%) used only one program while 4 patients (40%) preferred to have 2 programs in their stimulation portfolio. Three patients (30%) used only TONIC + BURST simultaneously. TONIC stimulation only was used by 2 patients (20%). TONIC + HF simultaneous combination was used by 1 patient (10%). Among the 4 patients who used 2 programs, 2 patients (20%) used TONIC + BURST combination and TONIC, 1 patient (10%) used TONIC + BURST combination and BURST and 1 patient (10%) used TONIC and BURST. In the SCStol group (n = 9), 6 patients (66.7%) used only one program while 2 patients (22.2%) used 2 programs and 1 patient (11.1%) used 3 programs. Four patients (44.4%) used only the TONIC + BURST combination therapy and 2 patients (22.2%) used only BURST stimulation. Among the 2 patients who preferred to have 2 programs in their stimulation portfolio, 1 patient (11.1%) used TONIC stimulation and TONIC + HF combination therapy and 1 patient (11.1%) used TONIC and TONIC + BURST combination. The 1 patient (11.1%) who preferred to use 3 programs used TONIC, BURST and HF stimulation.The comparisons between the two groups of waveforms applied can be found in n = 8), 3 patients (37.5%) used only one program while 5 patients (62.5%) preferred to have 2 programs in their stimulation portfolio. Two patients (25%) used only TONIC + BURST simultaneously and 1 patient (12.5%) used TONIC stimulation only (below the paresthesia threshold). Among the 5 patients who used 2 programs, 3 patients (37.5%) used TONIC + BURST combination and TONIC stimulation, 1 patient (12.5%) used TONIC + BURST combination and BURST and 1 patient (12.5%) used TONIC and BURST. In the SCStol group (n = 8), 6 patients (75%) used only one program while 2 patients (25%) used 2 programs. Six patients (75%) used only the TONIC + BURST combination therapy. Among the 2 patients who preferred to have 2 programs in their stimulation portfolio, 1 patient (12.5%) used TONIC stimulation and HF stimulation and 1 patient (12.5%) used TONIC stimulation and BURST stimulation.At the 3-month follow-up, in the LoC group (n = 8), 6 patients used only one program while 5 patients preferred to have 2 programs. Three patients (37.5%) used only TONIC + BURST combination therapy, 2 patients (25%) used TONIC stimulation only (below the paresthesia threshold for 1 patient) and 1 patient (12.5%) used TONIC + HF combination therapy. Among the 2 patients who used 2 programs, 1 patient (12.5%) used TONIC + BURST combination and TONIC stimulation and 1 patient (12.5%) used TONIC and BURST stimulation. In the SCStol group (n = 10), 8 patients (80%) used only one program while 2 patients (20%) used 2 programs. Four patients (40%) used only the TONIC + BURST combination therapy, 2 patients (20%) used only BURST stimulation, 1 patient (10%) used only BURST + HF combination therapy and 1 patient (10%) used only TONIC stimulation. Among the 2 patients who preferred to have 2 programs in their stimulation portfolio, 1 patient (10%) used TONIC stimulation and HF stimulation and 1 patient (10%) used TONIC stimulation and BURST stimulation.At the 6-month follow-up, in the LoC group (n = 8), 5 patients (62.5%) used only one program while 3 patients (37.5%) preferred to have 2 programs in their stimulation portfolio. Three patients (37.5%) used only TONIC + BURST combination therapy. TONIC stimulation only was used by 2 patients (25%) (under paresthesia threshold for 1 patient). Among the 3 patients who used 2 programs, 1 patient (12.5%) used TONIC + BURST combination and TONIC, 1 patient (12.5%) used TONIC + BURST combination and BURST and 1 patient (12.5%) used TONIC and BURST. In the SCStol group (n = 8), 6 patients (75%) used only one program while 2 patients (25%) used 2 programs. Four patients (50%) used only the TONIC + BURST combination therapy and 2 patients (25%) used only BURST stimulation. Among the 2 patients who preferred to have 2 programs in their stimulation portfolio, 1 patient (12.5%) used TONIC stimulation and HF stimulation and 1 patient (12.5%) used TONIC stimulation and BURST stimulation.At the 12-month follow-up, in the LoC group . Although Karri et al.  showed tIn this study we have reinforced findings previously published, with an added value of our ability to stratify FSCSS patients and to have performed subgroup analysis, allowed by 3D-computerized mapping data and objective metrics. The perspective of using 3D-computerized pain mapping assessment as part of the daily routine could make it possible to better understand the relationships between pain coverage and pain relief, thereby justifying two different electrical approaches, the objective being to modulate either spatial or temporal parameters, in two different patient populations . The main advantage of this approach resides in its versatility and flexibility. The possibility of combining several innovations in spatial and temporal adjustments, centralized by one technology, should be viewed as an opportunity to solve several patient concerns almost simultaneously. Using an example of one of the patients in this cohort, who was implanted with an adapter, the ability to provide (i) coverage recapturing, (ii) coverage extension, (iii) new pain onset coverage, (iv) comfort perception increase and (v) avoidance of positioning SCS effect, makes it quite easy to understand that the balance of risks/benefits between SCS lead revision, IPG systematic replacement and undergoing a new SCS screening trial thanks to an adapter, connected under local anesthesia, could be in favor when considering this approach, as a salvage therapy, when facing FSCSS. This was clearly documented using objective metrics in this study.All in all, these results need to be confirmed on a larger controlled prospective cohort with long-term follow-up .When patients are experiencing SCS LoE over time, several options can be discussed in a multidisciplinary pain reassessment, such as lead revision  or InterAs described in the introduction, FSCSS patients might observe LoE with or without LoC. This also largely depends on the type of SCS program(s) used: tonic stimulation and/or sub-paresthetic stimulation modalities. Some authors state that LoE is preferentially observed with patients using tonic stimulation . It is in = 11), which potentially leads to LoE, and, surprisingly, once again, independently of the waveform used. This lack/loss of coverage might also result from neural plasticity, but the fact that some neurons were adequately depolarized to create an analgesic effect initially, but not longer, could correspond to the notion of “SCS resistance” rather than “SCS tolerance”. There appears to be a physical, architectural change in the localization of the targeted fibers , and the fact that we were able to spatially recapture all patient sweet spots with adapters, and that they remained stable within time, shows that: (i) this is a spatial problem, and that (ii) it was probably a technological limitation in the method of delivering the electrical field, which was responsible for previous SCS device failure to recapture the new target. This spatial recapturing corresponds to a major added value of the technology connected to the adapter. Arising from this argumentation, we can conclude that LoE recovery, through LoC spatial recapturing, is clearly not to be attributed to any waveform change or temporal resolution adjustment of the electrical signal. We can thereby assume that “SCS resistance”, characterizing this first group of patients, is a topographic matter. This topographic matter has been addressed by spatial optimization of the signal in this study.− The first group includes patients facing LoC (TM)”, places a dynamic but constant electrical field along dorsal horn intra-spinal structures, in axial distribution, as well as a uniform electrical influence on longitudinal spinal cord tracts, thereby optimizing “sweet spot” targeting.− Examining the specificities of this new technology, the difference in terms of spatial targeting abilities, compared to other SCS systems, might come from anatomically guided neural targeting, using a three-dimensional finite element model of the spinal cord, derived from the Twente University computational bio-electrical model ,46. Thisn = 16), leading to another type of FSCSS. The notion of electric tolerance has been introduced more recently and is still the subject of debate. Tolerance could correspond either to local neurochemical adaptation to the electrical field delivered by the SCS lead [− The second group includes patients facing LoE, without LoC, who have developed the notion of “SCS tolerance” . As an echo to recent data regarding the interest of combination therapy and the ability to customize programs for patients so as to give them a certain level of autonomy to combine waveforms ,52 by cyMoreover, independently of the waveform chosen and used by the patients, the majority of these FSCSS patients, considered for this study, were complaining of LoE, without LoC, at their initial evaluation:In light of these study results, the optimization of the use of adapters, the target population and their place in our therapeutic armamentarium can be discussed. Our ambition is to describe general principles of a theoretical salvage algorithm , proposiFacing a chronic pain patient, already implanted with SCS, with a loss of efficacy due to loss of coverage, , after checking for impedance dysfunction and for lead potential displacement (with X-ray), we can propose to convert to an adapter and to use a spatial approach with MICC first, aiming to recapture the sweet spot, if possible , and to Facing a chronic pain patient, already implanted with SCS, with an adequate coverage but insufficient or lack of pain relief of their neuropathic pain component, our approach consists of: (i) checking impedance systematically  and checking hardware dysfunction (idem: no particular reason here since paresthesia cover the appropriate painful territory) and (ii) proposing conversion to a new screening trial, through adapters, allowing for temporal retargeting with a different technology, following the same modalities as those presented above, and if the trial is positive, SCS IPG is replaced without any change in the lead(s).We propose to reassess patients’ refractory to all available measures presented in this salvage algorithm ** in , in a MuIn case the indication of neurostimulation is still relevant, with positive predictive factors regarding patient selection, with no clear indication to any further surgery or invasive procedure to treat the potential pain generator and in the event that the conclusion of MDT assessment is oriented towards an SCS technical failure, which is not accessible to revision, one last option would be to discuss changing the anatomical target of neurostimulation , given the fact that 4 ports, instead of 2, are now available in this new generation of IPGs, making it possible to manage 4 different leads, with 32 contacts.Despite its originality, this study suffers from several limitations. First, our small sample size should be considered as nuancing the power of our results and consequently our interpretation. In addition, available waveform profiles were limited. Our limited sample size did not offer us the opportunity to have many patients/waveform groups and the relatively high number of available choices, especially when combination therapy is applied, cannot reflect all possibilities of stimulation modalities. However, interestingly, most patients went back to tonic, with or without a combination therapy. This must be confirmed on larger sample size studies. In addition, the retrospective nature of the study implies consideration of our promising results as a starting point for future prospective studies. The observational nature of the study led to an inability to control for unobserved confounders, a point which could be improved in future controlled randomized study designs.In case of FSCSS, with a patient implanted with hybrid stimulation , we could wonder if the potential new IPG, implanted following a positive lead trial, would not interfere with the other neurostimulation targets. Ongoing studies  and receThis study highlights the clear added value of implanting adapters to test alternative SCS modalities, when a patient is experiencing SCS failure despite good initial results, after checking hardware dysfunction and extensive SCS reprogramming with the existing implanted device. Whether FSCSS is a consequence of SCS resistance or of SCS tolerance, a salvage algorithm could guide patients and implanters, through a standardized reprogramming approach, towards a possible conversion from FSCSS back to an SCS success. Objective quantitative pain and paresthesia 3D mapping assessments appear to be of importance, in order to (i) more precisely document the potential cause of FSCSS, which might correspond to a specific patient profile, and (ii) to delineate objective comparisons between devices and targets, helping us to hierarchize our therapeutic options in the near future, by coupling these metrics into multidimensional composite pain indexes.Patent application N° PCT/EP2014/067231Patent application N° PCT/FR 14/000 186Patent application N° PCT/FR 14/000 187


Visual disturbances are commonly reported in patients with neck pain. Smooth pursuit neck torsion (SPNT) test performed in neutral position and with trunk rotated under the stationary head has been used to discriminate between those with cervical component and those without. However, no studies investigated the reliability of the SPNT-test in patients with chronic neck pain and healthy controls. The aim of this study was to assess inter-visit reliability of the SPNT-test while applying different amplitudes and velocities of target movement. Thirty-two controls and thirty-one patients were enrolled in the study. The SPNT-test was performed in neutral position and through 45° torsion positions. The test was performed at 20°/s, 30°/s and 40°/s velocities and at 30°, 40° and 50° amplitudes of cyclic sinusoidal target movements. Interclass correlation coefficient and smallest detectable change were calculated for parameters of gain and SPNT-differences. In patients, moderate to good reliability was observed for gain at 40° and 50° amplitudes and for 20°/s and 30°/s velocities, while moderate to excellent reliability for gain was observed in controls. Both groups presented with moderate to good reliability for SPNT-difference. Our findings imply that amplitudes of 40° and 50° and velocities of 20°/s and 30°/s are the most reliable and should be applied in future studies assessing oculomotor functions during the SPNT test. According to research and anecdotal evidence, patients with chronic neck pain frequently complain about different characteristics of visual disturbances such as blurred vision, words jumping on the page and difficulty focusing and concentrating on reading . These cAn important component of the oculomotor system is smooth pursuit eye movements . The tasThe SPNT test was first introduced in 1998 by Tjell and Rosenhall . The tesSince it was introduced the SPNT test has been frequently used to screen for deficiencies in eye movement control as a consequence of altered afferent input derived from cervical spine resulting in altered proprioceptive reflexes of the neck, the cervico-collic and cervico-ocular reflexes. Abnormal values of the test typically indicate error in proprioceptive information derived from the neck, transmitted by these reflexes. Over the years, many attempts have been made to elucidate deficits in oculomotor performance in patients with neck pain, but results remain inconclusive. Some researchers managed to find differences between patients and healthy individuals , while oSurprisingly, to our knowledge there is no research assessing test-retest reliability of the SPNT test which is a crucial component when reporting diagnostic validity. Smooth pursuit eye movement test has been shown to range from moderate  to good Sixty-four participants, of which thirty-two were patients with chronic neck pain  and thirty-two healthy individuals  participated in the study. Healthy participants were recruited among university staff, doctoral students and their friends. Patients with neck pain were referred by an orthopedic surgeon and were previously assessed for suitability via a telephonic interview. Each patient underwent an MRI, indicating some sort of lower cervical spine degenerative structural abnormality . Inclusion criteria for both groups were age range between 18 and 55 years. Subjects with chronic idiopathic neck pain having had to experience pain in the neck from 6 months to 5 years, were required to have at least 50 degrees of cervical rotation to both sides, a minimum score of 36 on the Dizziness Handicap Inventory out of 100 and a minimum score of 5 out of 10 on pain visual analogue scale (VAS). The VAS scale was a 10 cm horizontal line with ends marked “no pain” (left) and the “worst pain imaginable” (right) ,15. All A 100 Hz eye tracking device  was used to measure and record eye movements during smooth pursuit tasks. Prior to the experiment, a single target calibration routine was performed in the Tobii Pro Glasses Controller . Participants were required to track a red dot target  projected on a white screen using a projector  150 cm away at eye level. Subjects were sitting on a custom-made rotatable chair with upper body fixed to the back support. Hip angle was 80° of flexion, while their feet were placed flat on the floor. Measurements were conducted by the same examiner.Patients and healthy subjects answered Dizziness Handicap Inventory and were required to fill out a VAS of pain intensity. The testing protocol consisted of 3 different chair positions: (1) facing forward position , (2) eccentric rotation of the neck of 45° to the left and (3) to the right, respectively. The order of chair rotations was pseudo-randomized across subjects. In the neutral position the chair was aligned so that the participant was facing forward to the middle of the screen. During trunk rotation their head was in a neutral position while their trunk and lower body were rotated. All tests were performed in an isolated room with dim light.Before the test, all subjects performed 5 familiarization warm up cycles. For each condition subjects were required to track 10 cycles of cyclic sinusoidal target movements with 60 s rest intervals. Subjects were tested at 3 different maximal target speeds  and 3 different amplitudes of 30°, 40° and 50° in all 3 different chair positions, namely, neutral and rotation left and right, respectively. All tasks were performed in a random order. Each chair rotation was followed by a 5 min rest and a recalibration of the eye-tracking device. Participants completed the second oculomotor assessments with an average test-retest interval of 4 d (range 2–13 d).The eye movement data were filtered for blinks, saccades and fixations using Tobii Pro Lab software . The square waves  were removed from the eye movement data using custom-written software in Matlab . The eye movement data were fitted with a corresponding reference sinusoid with synchronized signal acquisition starting points. Each fitted sinusoid consisted of 10 cycles with correspondingly fixed amplitude (converted from angular degrees to pixels) and frequency that matched the profile for each individual condition. The horizontal eye movements were analyzed using gain, calculated as the ratio between fitted eye velocity amplitude and visual target velocity amplitude as described by Tjell et al. [Equation (1) gain neutral represents the average gain in the neutral position from the 6th to 9th cycle, Gain torsion L represents the average gain during the left neck torsion position from the 6th to 9th cycle and Gain torsion R represents the average gain during the right neck torsion position from the 6th to 9th cycle.Statistical analysis was performed in SPSS . Descriptive statistics (average and standard deviation) were calculated. Normality of distribution was analyzed separately using the Shapiro–Wilk test for each condition at each visit. A two-way mixed effect intraclass correlation coefficient for absolute agreement (ICC(3.1)) and a 95% confidence interval were used to ascertain reliability . An ICC In total, 32 healthy subjects and 32 patients with chronic neck pain were included for the inter-visit reliability study. However, one of the patients with chronic neck pain decided not to continue with further assessment after the first visit. Gain and SPNTdiff parameters were normally distributed in all conditions observed.1The results of the reliability analysis for the healthy subjects are presented in Results of the reliability study for the SPNTdiff in both groups are presented in Based on the results, it can be concluded that overall there is moderate to good inter-visit reliability for average gain in most conditions for both groups as presented in Most conditions with 50° amplitude of target movement showed superior reliability in both groups. This could be partially explained by the functional connections between extraocular and cervical muscle activity. In the study by Bexander and Hodges , neck muResults from our study show that neck pain patients had slightly poorer reliability than healthy individuals, but showed a similar trend where 50° amplitude of the SPNT test was most reliable. In addition to amplitude, eye movement velocity gives some further insights into reliability characteristics. Interestingly, both groups from our study presented with highest reliability in a neutral position when the target was moving at 30°/s that slightly increased when the trunk was rotated, which is in line with the above hypothesis. Similar findings about the reliability of the target movement velocity were found in the study by Ettinger et al. . Both grIn the study by Bargary et al.  reliabilAccording to the study by Treleaven et al. , pain inAn additional parameter investigated in this study was SPNTdiff. Based on the results, inter-visit reliability for SPNTdiff was lower than for gain in different conditions. In the patient group, reliability of SPNTdiff was moderate, while healthy controls presented with moderate to good ICC. These results were expected as SPNTdiff is calculated from average gain in neutral and in trunk rotated positions. By including three different parameters with their own errors of measurement, the cumulative error could increase and consequently weaken reliability. The most reliable conditions in both groups were at velocities of 20°/s and 30°/s and at amplitudes of 40° and 50°. This is in line with the above observations describing possible factors contributing to reliability of gain. As SPNTdiff is calculated for both sides and described as percentage of difference, possible unilateral structural abnormalities could influence results not considered in our study.Additionally, SDCg for gain was lower in healthy controls and higher in group of patients with chronic neck pain with no differences between conditions. Future studies should implement SDCg in smooth pursuit sensitivity studies comparing different groups of patients and healthy controls or effects of rehabilitation interventions. A similar trend was observed for SPNTdiff in patients with neck pain presenting with higher SDCg.Although an attempt was made to recruit a homogenous group of patients, neck pain disorders have heterogenous pathologies with interconnected signs and symptoms. Therefore, reliability of the SPNT test might vary across different neck pain pathologies. Future studies should include the most reliable parameters and use them for further assessments of the most sensitive parameters across different traumatic and non-traumatic neck pain incidences.