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Objective: Rehabilitation interventions for chronic pain typically include education, cognitive behavioural therapy, and exercise therapy, or a combination of these. A systematic review and meta-analysis of rehabilitation interventions for neuropathic pain was conducted. Design: Randomized controlled trials were identified in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and PsycINFO databases from inception up to 3 March 2022. Subjects/Patients: Adults with chronic (> 3 months) neuropathic pain. Methods: Primary outcomes were pain intensity, pain-related disability, and work participation. Secondary outcomes were quality of life, emotional strain, insomnia, and adverse outcomes, according to VAPAIN guidelines. Analyses were made post- intervention, which was defined as the assessment point immediately following the intervention or at the first-time measurement conducted after the intervention period. Results: In total, 15 studies (total population, n = 764) were incorporated. Most common interventions were cognitive behavioural programmes including acceptance and commitment therapy (n=4), n =4), mindfulness-based interventions (n n = 5), and yoga (n n = 2). Psychological interventions reduced both pain intensity (SMD -0.49, 95% CI -0.88 to -0.10) and pain-related disability (SMD -0.51, 95% CI -0.98 to -0.03), whereas other interventions had an effect on pain intensity but not on pain-related disability. Conclusion: Rehabilitation interventions, and psychological interventions in particular, seem to be of value for patients with chronic neuropathic pain., Funding Agencies|ALF Research Grants, Region Ostergotland [RO-962091]

Objectives - The aim of this study was to investigate a panel of inflammatory biomarkers in plasma from forklift truck operators (FLTOs) and healthy controls, and their relation to neck pain characteristics. Methods - From employees in a warehouse, 26 FLTOs were recruited and 24 healthy age- and sex-matched controls (CONs) were recruited via advertisement. The inclusion criterion for FLTOs was that they should operate reach decker and/or counterbalanced tilting mast forklift trucks. All participants were asked to answer a questionnaire covering demographic data, pain intensity numeric rating scale (NRS), anatomical spread, psychological distress, and health aspects. Pain sensitivity was measured using a pressure algometer. Blood samples were collected and analyzed for inflammatory proteins in plasma using a panel of 71 cytokines and chemokines. Multivariate data analysis including orthogonal partial least square-discriminant analysis (OPLS-DA) was performed to identify significant biomarkers. Results - Thirty percent of FLTOs reported NRS > 3 in the neck. Shoulder pain was common in 26% of the FLTOs. Pain and discomfort that most often prevented completion of activities were in the neck (20%), lower back (32%), and hips (27%). The FLTOs reported significantly (p = 0.04) higher levels of anxiety than the CON group and they had significantly lower pressure pain thresholds in the trapezius muscle on both right (p < 0.001) and left sides (p = 0.003). A significant OPLS-DA model could discriminate FLTOs from CON based on nine inflammatory proteins where the expression levels of four proteins were upregulated and five proteins were downregulated in FLTOs compared to CONs. Twenty-nine proteins correlated multivariately with pain intensity. Conclusions - The profile of self-reported health, pain intensity, sensitivity, and plasma biomarkers can discriminate FLTOs with pain from healthy subjects. A combination of both self-reported and objective biomarker measu, Funding Agencies|Medical Research Council of southeastern Sweden (FORSS); ALF Grants, Region Ostergotland

The Swedish Quality Registry for Pain rehabilitation (SQRP) is a well-established clinical registry for adult patients with complex chronic pain conditions. SQRP registers patient-reported outcome measures from a majority of specialist chronic pain units/departments in Sweden. Up to four International Classification of Diseases version 10 (ICD-10) diagnoses can be registered in SQRP. The aim of the paper is to describe how we envision the new chronic pain category MG30 in ICD-11 can be used in SQRP. We envision that the first diagnosis in SQRP shall always be a MG30 diagnosis, which will ensure broad implementation of ICD-11 in Swedish pain care. However, at first glance, there seems to be specificity problems with ICD-11 codes that might impair their useability in SQRP or other registries. But ICD-11 offers more than meets the eye. First, the entries at the level of the so-called foundational layer have unique resource identifiers (URI) that can be used to enhance specificity. Second, ICD-11 contains numerous extension codes that can be combined with the MG30 codes - for instance, concerning the anatomical location of pain. Third, to enrich the description of the clinical concept at hand, it is possible to create clusters of stem codes. These three options are briefly discussed. We conclude that the full potential of the MG30 category can be better exploited in registries such as SQRP if foundational codes, extension codes, and/or clustering of stem codes are used to enhance diagnostic specificity., Funding Agencies|ALF Grants, Region Ostergotland

Background: Factors that influence outcomes of interdisciplinary pain rehabilitation programs (IPRP) are poorly known. It is unclear how outcomes are influenced by pain intensity, psychological distress, and coping strategies.Aim: This clinical registry-based longitudinal cohort study has three aims: 1) to determine the relative importance of pain intensity, psychological distress, acceptance, and fear-avoidance for changes in three outcomes of IPRP at 12-month follow-up; 2) to investigate whether the effects of pain intensity and psychological distress on the three outcomes are mediated via acceptance and fear-avoidance; and 3) to determine whether sex is a moderator.Methods: This study uses Patient-Reported Outcome Measures (PROMs) from specialist units reporting data (2008-2016) to the Swedish Quality Registry for Pain Rehabilitation (SQRP). Adult chronic pain patients (N = 1991) answered the PROMs (background, pain, psychological distress, coping, participation, and health-related quality of life (HRQoL)). Partial Least Squares Structural Equation Modelling (PLS-SEM) was used to explore the aims.Results: Changes in acceptance (13:0.424-0.553; all P<0.001) were the strongest predictor of the three outcomes (changes in life control, interference, and HRQoL) at 12-month follow-up. The next strongest predictor was baseline acceptance (13: 0.177-0.233; all P<0.001) and changes in fear-avoidance (13: -0.152- -0.186; all P<0.001). Baseline pain intensity and psychological distress showed weak positive associations. Their effects on the three outcomes were mediated via acceptance aspects. Sex was not a moderator.Discussion and Conclusion: Acceptance aspects (baseline and changes) were important predictors of IPRP outcomes. Changes in fear-avoidance were also important although to a lesser degree. Some of the effects of pain intensity and psychological distress on outcomes were mediated via acceptance at baseline. Future PLS-SEM analysis of real-worl

N-arachidonoylethanolamine (also known as anandamide) and 2-arachidonoylglycerol are activators of the cannabinoid receptors. The endocannabinoid system also includes structurally and functionally related lipid mediators that do not target cannabinoid receptors, such as oleoylethanolamide, palmitoylethanolamide, and stearoylethanolamide. These bioactive lipids are involved in various physiological processes, including regulation of pain. The primary aim of the study was to analyze associations between serum levels of these lipids and pain in participants in the Pain in Neuropathy Study, an observational, cross-sectional, multicentre, research project in which diabetic patients with painless or painful neuropathy underwent deep phenotyping. Our hypothesis was that painful neuropathy would be associated with higher levels of the 5 lipids compared with painless neuropathy. Secondary aims were to analyze other patient-reported outcome measures and clinical data in relationship to lipid levels. The lipid mediators were analyzed in serum samples using liquid chromatography tandem mass spectrometry (LC-MS/MS). Serum levels of anandamide were significantly higher in the painful group, but the effect size was small (Cohen d = 0.31). Using cluster analysis of lipid data, patients were dichotomized into a "high-level" endocannabinoid group and a "low-level" group. In the high-level group, 61% of patients had painful neuropathy, compared with 45% in the low-level group (P = 0.039). This work is of a correlative nature only, and the relevance of these findings to the search for analgesics targeting the endocannabinoid system needs to be determined in future studies., Funding Agencies|NEURO Sweden; ALF Grants; Swedish Research Council [2018-02470]; MRC and vs Arthritis [MR/W002388/1]; European Union [FP7/2007-2013]; European Commission Horizon 2020 [ID633491]; Novo Nordisk Foundation Challenge Program grant [NNF14OC0011633]; Academy of Medical Sciences Starter Grant [SGL022\1086]; Honorary Senior Research Fellow and Carnegie-Wits Diaspora Fellow; Wellcome Trust [083259]

Objectives This explorative study analyses interrelationships between peripheral compounds in saliva, plasma, and muscles together with body composition variables in healthy subjects and in fibromyalgia patients (FM). There is a need to better understand the extent cytokines and chemokines are associated with body composition and which cytokines and chemokines differentiate FM from healthy controls.Methods Here, 32 female FM patients and 30 age-matched female healthy controls underwent a clinical examination that included blood sample, saliva samples, and pain threshold tests. In addition, the subjects completed a health questionnaire. From these blood and saliva samples, a panel of 68 mainly cytokines and chemokines were determined. Microdialysis of trapezius and erector spinae muscles, phosphorus-31 magnetic resonance spectroscopy of erector spinae muscle, and whole-body magnetic resonance imaging for determination of body composition (BC)-i.e., muscle volume, fat content and infiltration-were also performed.Results After standardizing BC measurements to remove the confounding effect of Body Mass Index, fat infiltration and content are generally increased, and fat-free muscle volume is decreased in FM. Mainly saliva proteins differentiated FM from controls. When including all investigated compounds and BC variables, fat infiltration and content variables were most important, followed by muscle compounds and cytokines and chemokines from saliva and plasma. Various plasma proteins correlated positively with pain intensity in FM and negatively with pain thresholds in all subjects taken together. A mix of increased plasma cytokines and chemokines correlated with an index covering fat infiltration and content in different tissues. When muscle compounds were included in the analysis, several of these were identified as the most important regressors, although many plasma and saliva proteins remained significant.Discussion Peripheral factors were important for group diffe, Funding Agencies|Swedish Research Council

Objective: Chronic pain is a common manifestation of Ehlers-Danlos syndrome and hypermobility spectrum disorders; thus it is often suggested that patients undergo generic interdisciplinary pain rehabilitation, despite there being little evidence to support this decision. The aim of this study is to examine the effectiveness of standard rehabilitation programmes for chronic pain on patients with Ehlers-Danlos syndrome and hypermobility spectrum disorders, compared with patients with other chronic pain disorders. Subjects: Data, collected between 2008 and 2016, were extracted from a Swedish national registry. The patient data comprised of 406 cases with Ehlers-Danlos syndrome or hypermobility spectrum disorders, 784 cases with a whiplash-related diagnosis, 3713 cases with diagnoses relating to spinal pain, and 2880 cases of fibromyalgia. Methods: The differences between groups on key outcome measures from pre-to 1-year follow-up after interdisciplinary pain rehabilitation were analysed using linear mixed effects models. Sensitivity analysis in the form of pattern-mixture modelling was conducted to discern the impact of missing data. Results: No significant differences were found in improvements from pre-to 1-year follow-up for patients with Ehlers-Danlos syndrome or hypermobility spectrum disorder compared with other diagnostic groups regarding measures of health-related quality of life, mental health, or fatigue. At follow-up, differences in pain interference (d = –0.34 (95% confidence interval [95% CI] –0.5 to –0.18)), aver-age pain (d = 0.22 (95% CI 0.11–0.62)) and physical functioning (d = 2.19 (95% CI 1.61–2.77)) were detected for the group with spinal-related diagnoses in relation to those with EDS/HSD, largely due to pre-treatment group differences. Sensitivity analysis found little evidence for missing data influencing the results. Conclusion: This study suggests that patients with Ehlers-Danlos syndrome/hypermobility spectrum disorders may benefit from inclus

Objectives: Internet-delivered psychological interventions can be regarded as evidence-based practices and have been implemented in psychiatric and somatic care at primary and specialist levels. However, challenges as low adherence and poor routinization, have arisen during attempts to implement internet-delivered interventions in chronic pain settings. Internet-delivered Acceptance and Commitment Therapy (IACT) has been found to be helpful for chronic pain patients and might aid in developing pain rehabilitation services. However, the integration of IACT into standard health care has not yet been described from an implementation science perspective. The aim of this hybrid 1 effectiveness-implementation study was to evaluate the process of implementing IACT in a pain rehabilitation setting, to guide future implementation initiatives.Methods: In this retrospective study we described actions taken during an implementation initiative, in which IACT was delivered as part of an interdisciplinary pain rehabilitation program (IPRP) at a specialist level clinic. All documents relevant to the study were reviewed and coded using the Quality Improvement Framework (QIF), focusing on adoption, appropriateness and sustainability.Results: The QIF-analysis of implementation actions resulted in two categories: facilitators and challenges for implementation. Sustainability may be facilitated by sensitivity to the changing needs of a clinical setting and challenged by unfitting capacity building. Appropriateness might be challenged by an insufficient needs assessment and facilitated by aligning routines for communication with the clinics existing infrastructure. Adoption may be facilitated by staff key champions and an ability to adapt to occurring hurdles. Possible influential factors, hypotheses and key process challenges are presented in a logic model to guide future initiatives.Conclusions: Sustainable implementation may depend on both the continuity of facilitating implementation, Funding Agencies|Swedish Social Insurance Agency; Ministry of Health and Social Affairs; Swedish Association of Local Authorities and Regions; Vardal Foundation [99368-2009/RS10]; Lions Ostergotland Sweden [2020-01334]; City Council of Ostergotland, Sweden [LIO-938308, SC-2019-00155-39]

Dysfunctional top-down pain modulation is a hallmark of fibromyalgia (FM) and physical exercise is a cornerstone in FM treatment. The aim of this study was to explore the effects of a 15-week intervention of strengthening exercises, twice per week, supervised by a physiotherapist, on exercise-induced hypoalgesia (EIH) and cerebral pain processing in FM patients and healthy controls (HC). FM patients (n = 59) and HC (n = 39) who completed the exercise intervention as part of a multicenter study were examined at baseline and following the intervention. Following the exercise intervention, FM patients reported a reduction of pain intensity, fibromyalgia severity and depression. Reduced EIH was seen in FM patients compared to HC at baseline and no improvement of EIH was seen following the 15-week resistance exercise intervention in either group. Furthermore, a subsample (Stockholm site: FM n = 18; HC n = 19) was also examined with functional magnetic resonance imaging (fMRI) during subjectively calibrated thumbnail pressure pain stimulations at baseline and following intervention. A significant main effect of exercise (post > pre) was observed both in FM patients and HC, in pain-related brain activation within left dorsolateral prefrontal cortex and caudate, as well as increased functional connectivity between caudate and occipital lobe bordering cerebellum (driven by the FM patients). In conclusion, the results indicate that 15-week resistance exercise affect pain-related processing within the cortico-striatal-occipital networks (involved in motor control and cognition), rather than directly influencing top-down descending pain inhibition. In alignment with this, exercise-induced hypoalgesia remained unaltered.

Funding: Swedish Research Council; Knut and Alice Wallenberg Foundation; ALF Grants; Region OEstergoetland; Svenska Laekaresaellskapet; Western Sydney University

Background: Cerebrospinal fluid (CSF) can reasonably be hypothesized to mirror central nervous system pathophysiology in chronic pain conditions. Metabolites are small organic molecules with a low molecular weight. They are the downstream products of genes, transcripts and enzyme functions, and their levels can mirror diseased metabolic pathways. The aim of this metabolomic study was to compare the CSF of patients with chronic neuropathic pain (n = 16) to healthy controls (n = 12). Methods: Nuclear magnetic resonance spectroscopy was used for analysis of the CSF metabolome. Multivariate data analysis by projection discriminant analysis (OPLS-DA) was used to separate information from noise and minimize the multiple testing problem. Results: The significant OPLS-DA model identified 26 features out of 215 as important for group separation (R2 = 0.70, Q2 = 0.42, p = 0.017 by CV-ANOVA; 2 components). Twenty-one out of twenty-six features were statistically significant when comparing the two groups by univariate statistics and remained significant at a false discovery rate of 10%. For six out of the top ten metabolite features, the features were absent in all healthy controls. However, these features were related to medication, mainly acetaminophen (=paracetamol), and not to pathophysiological processes. Conclusion: CSF metabolomics was a sensitive method to detect ongoing analgesic medication, especially acetaminophen., Funding Agencies|The support of Swedish NMR Centre at the University of Gothenburg, Gothenburg, Sweden, is hereby acknowledged.; Swedish NMR Centre at the University of Gothenburg, Gothenburg, Sweden

BackgroundBoth chronic pain and depressive and/or anxiety symptoms are associated with negative impacts on daily living, including interference and lack of life control. However, little is known about how pain and psychological distress affect these impacts.AimThe first aim was to assess how pain intensity, psychological distress, and social support interact with interference and lack of life control. A second aim was to investigate whether the strength of these relationships is moderated by the presence or absence of depression and/or anxiety.Subjects and methodsPatient-Reported Outcome Measures (PROMs), which are available in the Swedish Quality Registry for Pain Rehabilitation (SQRP), were retrieved for patients with chronic pain (N = 40,184). A theoretical model with the constructs/latent variables pain intensity, psychological distress, interference, lack of life control, and social support was proposed and analyzed using Partial Least Squares Structural Equation Modelling (PLS-SEM). Indicators for these constructs were identified from the PROMs of the SQRP. Two models of the total cohort, which differed with respect to the causal relationship between pain intensity and psychological distress, were investigated. The moderating effects of anxiety and/or depression were also analyzed.ResultsRelatively low correlation and explanatory power (R-2 = 0.16) were found for the pain intensity-psychological distress relationship. Pain intensity had a stronger effect on interference than on lack of life control. The reverse was found for psychological distress - i.e., psychological distress seemed to have a higher negative influence on function than on interference. The underlying assumption of the causal relationship between pain intensity and psychological distress determined how strong pain intensity and psychological distress influenced interference and lack of life control. Social support showed very similar absolute significant correlations with interference and lack

IntroductionFibromyalgia causes long-term pain. It affects at least 2% of the population, the majority being women. In addition, extended symptoms corresponding to vitamin B-12 deficiency occur. Findings from several studies have indicated that vitamin B-12 may be a possible treatment for pain in fibromyalgia. The aim of the proposed study is to evaluate whether vitamin B-12 decreases pain sensitivity and the experience of pain (ie, hyperalgesia and allodynia) in women with fibromyalgia.Methods and analysisThe study is a randomised, placebo-controlled, single-blind, clinical trial with two parallel groups which are administered mecobalamin (vitamin B-12) or placebo over 12 weeks. 40 Swedish women aged 20-70 years with an earlier recorded diagnosis of fibromyalgia are randomised into the placebo group or the treatment group, each consisting of 20 participants. Outcomes consist of questionnaires measured at baseline and after 12 weeks of treatment. A final re-evaluation will then follow 12 weeks after treatment ends. The primary outcome is tolerance time, maximised to 3min, which is assessed using the cold pressor test. In order to broaden the understanding of the lived experience of participants, qualitative interviews will be conducted using a phenomenological approach on a lifeworld theoretical basis (reflective lifeworld research approach).Ethics and disseminationThe protocol for the study is approved by the local ethical committee at Linkoping (EPM; 2018/294-31, appendices 2019-00347 and 2020-04482). The principles of the Helsinki Declaration are followed regarding oral and written consent to participate, confidentiality and the possibility to withdraw participation from the study at any time. The results will primarily be communicated through peer-reviewed journals and conferences.Trial registration number NCT05008042., Funding Agencies|Medical Research Council of Southeast Sweden [479961, 656241, 854911]; Capio Research Foundation, Sweden [2018-3195, 2019-3277]

BackgroundSleep problems (insomnia) and chronic pain are associated. Chronic pain and insomnia/insufficient sleep quality share similar symptoms and features. Although they have a bidirectional relationship, more research is needed to understand how they interact via mediators and how moderators influence this relationship.AimsIn this large clinical registry-based cohort study (N = 6,497), we investigate important mediators between insomnia and pain intensity in a cross-sectional sample of chronic pain patients using advanced path analysis. In addition, we investigate whether some background variables were moderators of the identified important paths or not and the correlation patterns between insomnia and pain intensity in relation to the mediators.MethodsThis study includes a cohort of adult patients with chronic non-cancer pain from the Swedish Quality Registry for Pain Rehabilitation (SQRP) with data on patient-reported outcome measures (PROMs) (2008-2016). The PROMs cover the background, pain aspects, psychological distress, pain-related cognitions, activity/participation, and health-related quality of life variables of the patients. Partial least squares structural equation modeling was used to explore the direct and indirect (via mediators) relationships between insomnia and pain intensity at baseline.ResultsIn this cohort study, insomnia was prevalent at 62.3%, and both direct and indirect mediating paths were present for the insomnia-pain intensity relationship. All of the mediating effects combined were weaker than the direct effect between insomnia and pain intensity. The mediating effects via catastrophizing and acceptance showed the strongest and equal mediating paths, and mediating effects via fear avoidance were the second strongest. Insomnia showed stronger direct significant correlations with psychological distress, catastrophizing, and acceptance compared with those of pain intensity. Sex, age, education level, spatial extent of pain, or body mass

OBJECTIVE To systematically assess credibility and certainty of associations between cannabis, cannabinoids, and cannabis based medicines and human health, from observational studies and randomised controlled trials (RCTs). DESIGN Umbrella review. DATA SOURCES PubMed, PsychInfo, Embase, up to 9 February 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Systematic reviews with meta-analyses of observational studies and RCTs that have reported on the efficacy and safety of cannabis, cannabinoids, or cannabis based medicines were included. Credibility was graded according to convincing, highly suggestive, suggestive, weak, or not significant (observational evidence), and by GRADE (Grading of Recommendations, Assessment, Development and Evaluations) (RCTs). Quality was assessed with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). Sensitivity analyses were conducted. RESULTS 101 meta-analyses were included (observational=50, RCTs=51) (AMSTAR 2 high 33, moderate 31, low 32, or critically low 5). From RCTs supported by high to moderate certainty, cannabis based medicines increased adverse events related to the central nervous system (equivalent odds ratio 2.84 (95% confidence interval 2.16 to 3.73)), psychological effects (3.07 (1.79 to 5.26)), and vision (3.00 (1.79 5.03)) in people with mixed conditions (GRADE=high), improved nausea/vomit, pain, spasticity, but increased psychiatric, gastrointestinal adverse event, and somnolence among others (GRADE=moderate). Cannabidiol improved 50% reduction of seizures (0.59 (0.38 to 0.92)) and seizure events (0.59 (0.36 to 0.96)) (GRADE=high), but increased pneumonia, gastrointestinal adverse events, and somnolence (GRADE=moderate). For chronic pain, cannabis based medicines or cannabinoids reduced pain by 30% (0.59 (0.37 to 0.93), GRADE=high), across different conditions (n=7), but increased psychological distress. For epilepsy, cannabidiol increased risk of diarrhoea (2.25 (1.33 to 3.81)), had no effect on sleep disru