Eleven neurology-related proteins measured in serum are positively correlated to the severity of diabetic neuropathy.

About 20% of patients with diabetes suffer from chronic pain with neuropathic characteristics. We investigated the multivariate associations between 92 neurology-related proteins measured in serum from 190 patients with painful and painless diabetic neuropathy. Participants were recruited from the Pain in Neuropathy Study, an observational cross-sectional multicentre study in which participants underwent deep phenotyping. In the exploration cohort, two groups were defined by hierarchical cluster analyses of protein data. The proportion of painless vs painful neuropathy did not differ between the two groups, but one group had a significantly higher grade of neuropathy as measured by the Toronto Clinical Scoring System (TCSS). This finding was replicated in the replication cohort. Analyzing both groups together, we found that a group of 11 inter-correlated proteins (TNFRSF12A, SCARB2, N2DL-2, SKR3, EFNA4, LAYN, CLM-1, CD38, UNC5C, GFR-alpha-1, and JAM-B) were positively associated with TCSS values. Notably, EFNA4 and UNC5C are known to be part of axon guidance pathways. To conclude, although cluster analysis of 92 neurology-related proteins did not distinguish painful from painless diabetic neuropathy, we identified 11 proteins which positively correlated to neuropathy severity and warrant further investigation as potential biomarkers.

The new chronic pain MG30 category and diagnostic specificity in quality registries-problems and suggested solutions with special reference to Swedish Quality Registry for Pain rehabilitation (SQRP).

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.

Should cancer pain still be considered a separate category alongside acute pain and chronic non-cancer pain? Reflections on ICD-11.

Introduction: Traditionally, cancer pain has often been viewed as an independent third major category in pain medicine alongside acute pain and chronic non-cancer pain. However, the new chronic pain category MG30 in the eleventh version of International Classification of Diseases (ICD-11) includes cancer-related pain as one of its seven subgroups. In light of this, the aim of the paper is to investigate whether the traditional trichotomy should be replaced by a dichotomy between acute pain and chronic pain, cancer-related pain being part of both groups depending on the duration of pain. Methods: The rationale for viewing cancer pain as a separate category is reviewed. Results: Cancer being a deadly disease, cancer pain has a life-and-death and existential dimension that is different from non-cancer pain. It seems sensible to believe that this is an additional dimension to the suffering caused by cancer pain, and that clinicians should therefore take this existential dimension into consideration when assessing pain. Conclusion: Without challenging the place of chronic cancer-related pain under the MG30 heading, it is concluded that while using ICD-11 in the future, pain clinicians should continue being mindful of the fact that the reality of death shapes the experience of cancer pain. The traditional trichotomy is therefore still valid and mirrors the fact that human beings are vulnerable (acute pain), temporal (chronic pain) and mortal (cancer pain).

Tonic cuff pressure pain sensitivity in chronic pain patients and its relation to self-reported physical activity.

OBJECTIVES: Physical inactivity is a global health concern and a significant problem among chronic pain patients. They often experience pain flare-ups when they try to increase their physical activity level. Most research on the relationship between pain sensitivity and physical activity has been on healthy participants. Data on chronic pain patients are lacking. Using cuff pressure algometry, this study investigated tonic cuff pressure pain sensitivity and its associations to self-reported physical activity and other patient-reported outcomes in chronic pain patients. METHODS: Chronic pain patients (n=78) were compared to healthy controls (n=98). Multivariate data analysis was used to investigate the associations between tonic cuff pressure pain sensitivity, physical activity, and other patient-reported outcome measures. RESULTS: The three most important variables for group discrimination were perceived health status (EQVAS: p(corr)=-0.85, i.e., lower in patients), depression (HADS-D: p(corr)=0.81, i.e., higher in patients), and the tonic cuff pressure pain sensitivity variable maximum pain intensity (VAS-peak-arm: p(corr)=0.75, i.e., higher in patients). In patients, the most important predictors for high VAS-peak-arm were female sex (p(corr)=-0.75), higher number of painful regions (p(corr)=0.72), higher pain intensity (p(corr)=0.55), followed by lower level of self-reported physical activity (p(corr)=-0.39). VAS-peak-arm in patients correlated negatively with self-reported physical activity (rho=-0.28, p=0.018). CONCLUSIONS: Physical activity may be the most important patient-changeable variable correlating to pain sensitivity. This study highlights the importance of more research to further understand how increased physical activity may decrease pain sensitivity in chronic pain patients.

Serum levels of endocannabinoids and related lipids in painful vs painless diabetic neuropathy: results from the Pain in Neuropathy Study.

ABSTRACT: 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.

Chronic Pain and Time - A Theoretical Analysis.

Background: When theoretically discussing pain, the distinction between acute and chronic pain is not always taken into consideration. By contrast, informed by the pain medicine distinction between acute and chronic pain, the present theoretical paper analyses the phenomena of chronicity and chronification in the pain setting. Methods: Philosopher Fredrik Svenaeus and his paper The phenomenology of chronic pain: embodiment and alienation (Continental Philosophy Review 2015;48:107-122) is used as a dialogue partner. Results: Three aspects, relevant for clinicians, are discussed: (1) the distinction between emotion and mood, arguing that the process of chronification entails pain evolving from the former to the latter; (2) chronification as a process in which the pain patient becomes aware of his/her temporality, both the past and the future coming to the fore (as opposed to severe acute pain in which only the present counts, ie, getting rid of the pain now); (3) the acquisition of a pain-related narrative identity, interdisciplinary pain rehabilitation programs being described as helping patients regain a narrative identity that is not dominated by pain or by a fruitless chase after pain relief. Conclusion: Chronic pain reminds us of our temporality and of the narrative character of our lives.

[Chronic pain as a disease: An overview of pain diagnoses in ICD-11]. / Långvariga smärttillstånd får ny klassifikation i ICD-11.

Pain is a symptom that can be associated with dangerous diseases such as cancer. Hence, to avoid delay in diagnosis of an underlying serious condition, it is important to be thorough when assessing pain. However, all pains are not symptoms of an underlying disease. Instead, many chronic pain conditions can be viewed as diseases in their own right. Indeed, sometimes the pain is the disease - such is for instance the case for fibromyalgia, painless fibromyalgia being a contradiction in terms. The new classification of chronic pain conditions according to the eleventh version of International Classification of Diseases (ICD-11) is presented and discussed. It is argued that the classification makes pain medicine visible as an academic discipline; that it may contribute to a legitimization process in which the suffering of pain patients is recognized semantically and taxonomically; and that it opens up new research possibilities in the chronic pain field.

Cerebrospinal Fluid Metabolomics Identified Ongoing Analgesic Medication in Neuropathic Pain Patients.

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.

Biomarkers in Pain.

The focus of this Special Issue on Biomedicines is on the value of "Biomarkers in Pain" from a broad perspective [...].

[Chronic pain and its relationship with anxiety and depression]. / Långvarig smärta ­ relationen till ångest och depression är komplex.

Depression and anxiety are highly prevalent in chronic pain. Clinicians often interpret depression/anxiety as consequences of chronic pain, but some psychiatrists contend that the consequence hypothesis is overrated and that psychiatric symptoms in pain patients should be understood as part of the psychiatric disease. In this overview, the potential bidirectional nature of the relationship between chronic pain and depression/anxiety is discussed on a conceptual level. Two additional possible ways of understanding the relationship are presented: psychological vulnerability can be a risk factor for the chronification of pain, and an underlying mild chronic pain can be exacerbated when the patient encounters a new psychosocial stressor. In clinical practice, it is important not to get stuck in a fruitless chase for a causal understanding. However, it is of great value for clinicians to reflect upon the complexity and dynamic nature of the relationship between pain and depression/anxiety.

Effects of interdisciplinary pain rehabilitation programs on neuropathic and non-neuropathic chronic pain conditions - a registry-based cohort study from Swedish Quality Registry for Pain Rehabilitation (SQRP).

BACKGROUND AND AIM: Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system. Pharmacological treatments for neuropathic pain often fail despite following guidelines. Interdisciplinary Pain Rehabilitation Programs (IPRP) are an effective intervention for chronic pain conditions. Little research has investigated whether IPRP can benefit patients with chronic neuropathic pain compared to other chronic pain conditions. This study assesses the real-world effects of IPRP on patients with chronic neuropathic pain compared to non-neuropathic patients using Patient-Reported Outcome Measures (PROMs) available in the Swedish Quality Registry for Pain Rehabilitation (SQRP). METHODS: A neuropathic group of patients (n = 1,654) were identified in two steps. This group was compared to a non-neuropathic group (n = 14,355) composed of common diagnoses (low back pain, fibromyalgia, whiplash associated disorders, and Ehlers-Danlos Syndrome) in relation to background variables, three overall outcome variables, and mandatory outcome variables (pain intensity, psychological distress symptoms, activity/participation aspects and health-related quality of life variables). Of these patients 43-44% participated in IPRP. RESULTS: At assessment, the neuropathic group reported significantly (with small effect sizes (ES)) more physician visits the previous year, older age, shorter pain durations, and less spatial extent of the pain (moderate ES). Moreover, for the 22 mandatory outcome variables, we found only clinically insignificant differences according to ESs between the groups. For patients participating in IPRP, the neuropathic group displayed equal or in some cases slightly superior results compared to the non-neuropathic group. DISCUSSION AND CONCLUSION: After assessing the real-world effects of IPRP, this large study found that neuropathic pain patients can benefit from the IPRP intervention. Both registry studies and RCTs are needed to better understand which patients with neuropathic pain are most suitable for IPRP and to what extent special considerations need to be made for these patients within the framework of IPRP.

The benefits and risks of nostalgia: analysis of a fictional case with special reference to ethical and existential issues.

BACKGROUND: In a previous paper in Philos Ethics Humanit Med, the 1937 Swedish novel Sömnlös (Swedish for sleepless) by Vilhelm Moberg was used as background for a thought experiment, in which last century's progresses concerning the safety of sleeping pills were projected into the future. This gave rise to a theoretical discussion about broad medico-philosophical questions such as (among other things) the concept of pharmaceuticalisation. METHODS: In this follow-up paper, the theme of insomnia in Sömnlös is complemented by a discussion of the concept of nostalgia. The core of the paper is a theoretical discussion about the benefits and risks of nostalgia, bringing together some aspects of recent psychological research about the construct of nostalgia with the main story line of the novel. RESULTS AND CONCLUSION: Nostalgia is portrayed as being, in some sense at least, ultimately beneficial for the protagonist of Sömnlös. This is congruent with recent psychological research. However, the story also shows that nostalgia may lead to problematic behaviours, at least when viewed from a virtue ethics perspective. Hence, nostalgia is both what leads the protagonist into ethically problematic behaviour and that which (paradoxically) ultimately saves him from his initial lack of courage, justice, temperance and practical wisdom. Moreover, the protagonist does not only "grow" ethically but also existentially. Hence, the novel opens up the possibility that insomnia and nostalgia might be viewed as bearers of important existential information (cf. sociologist of religion Peter L. Berger and his concept of "signals of transcendence").

Pain assessment 3 × 3: a clinical reasoning framework for healthcare professionals.

OBJECTIVES: To give an overview of central aspects of pain medicine-specific clinical reasoning when assessing a pain patient. Clinical reasoning is the thinking and decision-making processes associated with clinical practice. METHODS: Three core pain assessment areas that are crucial for clinical reasoning in the field of pain medicine are discussed, each of them consisting of three points. RESULTS: First, it is important to distinguish acute, chronic non-cancer, and cancer-related pain conditions. This classical and very simple trichotomy still has important implications treatment-wise, e.g., concerning the use of opioids. Second, the pain mechanism needs to be assessed. Is the pain nociceptive, neuropathic, or nociplastic? Simply put, nociceptive pain has to do with injury of non-neural tissue, neuropathic pain is caused by a disease or lesion of the somatosensory nervous system, and nociplastic pain is believed to be related to a sensitized nervous system (c.f. the concept of "central sensitization"). This also has implications concerning treatment. Some chronic pain conditions are nowadays viewed more as diseases rather than the pain being merely a symptom. In the new ICD-11 pain classification, this is conceptualized by the characterization of some chronic pains as "primary". Third, in addition to a conventional biomedical evaluation, psychosocial and behavioral aspects must also be assessed, the pain patient being viewed as an active agent and not merely as the passive recipient of an intervention. Hence, the importance of a dynamic bio-psycho-social perspective. The dynamic interplay of biological, psychological, and social aspects must be taken into account, putative behavioral "vicious circles" thereby being identified. Some core psycho-social concepts in pain medicine are mentioned. CONCLUSIONS: The clinical applicability and clinical reasoning power of the 3 × 3 framework is illustrated by three short (albeit fictional) case descriptions.

Teaching the biopsychosocial model of chronic pain: Whom are we talking to?

The biopsychosocial (BPS) model of chronic pain can be illustrated in many ways. Our aim is to adapt three illustrations of the BPS approach selected from the literature to target different groups: patients, health professionals and clinical trainees. In clinician-patient consultations, we use an illustration which shows the interactions among the BPS domains in the creation of suffering and pain behaviours in a "vicious spiral". Moreover, we help our patients understand chronic pain often does not entail remaining tissue damage. In clinical practice, we communicate to other health professionals that the relative contribution of each BPS domain varies from patient to patient. This disproportional contribution may also change dynamically over the time. In teaching clinical trainees, we combine thoroughness (i.e., focus on "details") with an understanding of the "dynamics" of pain chronification/chronic pain, i.e., focus on helping the trainee identify the mutual and joint interactions between different parts of the BPS framework. CONCLUSION: The three illustrations can be used as pedagogical tools for better-informed BPS perspectives in different settings. PRACTICE IMPLICATIONS: Clinicians need to be keen observers and adapt their communication depending on whom they are talking to.

The treatment lottery of chronic back pain? A case series at a multidisciplinary pain centre.

OBJECTIVES: Despite the number of people affected by chronic back pain, and the many available treatment options, even the best modalities provide limited pain reduction on a group level, often without simultaneous improvements in functioning or health-related quality of life. The objective was to provide an overview of the treatment of chronic back pain in clinical practice at a multidisciplinary pain centre, and to study patient and pain characteristics in different treatment groups. METHODS: 104 chronic back pain patients (primary ICD-10-SE-diagnosis M53.0-M54.9 excluding M54.1 and M54.3), referred to the Pain and Rehabilitation Centre, University Hospital, Linköping in 2015, were studied using data from the Swedish Quality Registry for Pain Rehabilitation, self-reported medication data, and a retrospective medical record review. RESULTS: The following treatment groups were identified: rehabilitation (n=21), analgesics (n=33), invasive intervention (n=14), and no treatment (n=35). Significant differences between groups were found with regards to age, sick leave, education level, persisting pain duration, punishing responses by significant other, previous invasive intervention, receiving sub-clinic, physician speciality and referring care level. CONCLUSIONS: Overall, patient demographics were associated with treatment strategy to a higher degree than patient-reported outcome measures. Moreover, physician speciality and organisational factors seemed to play a role in treatment choice.

An investigation of metabolome in blood in patients with chronic peripheral, posttraumatic/postsurgical neuropathic pain.

Neuropathic pain (NP) is a chronic pain condition resulting from a lesion or disease in the somatosensory nervous system. The aim of this study was to investigate the metabolome in plasma from patients with chronic peripheral, posttraumatic/postsurgical NP compared to healthy controls. Further, we aimed to investigate the correlation between pain intensity and the metabolome in plasma. The metabolic profile in plasma samples from 16 patients with chronic NP and 12 healthy controls was analyzed using a nuclear magnetic resonance spectroscopy method. Information about pain intensity, pain duration, body mass index (BMI), age, sex, and blood pressure were obtained through a questionnaire and clinical examination. Multivariate data analysis was used to identify metabolites significant for group separation and their correlation with pain intensity and duration, BMI, and age. We found 50 out of 326 features in plasma significantly contributing to group discrimination between NP and controls. Several of the metabolites that significantly differed were involved in inflammatory processes, while others were important for central nervous system functioning and neural signaling. There was no correlation between pain intensity and levels of metabolite in NP. These findings indicate that there seems to be peripheral/systemic differences in the metabolic profile between patients with chronic NP and healthy individuals.

Plasma proteins from several components of the immune system differentiate chronic widespread pain patients from healthy controls - an exploratory case-control study combining targeted and non-targeted protein identification.

Chronic widespread pain (CWP), including fibromyalgia (FM), is characterized by generalized musculoskeletal pain and hyperalgesia. Plasma proteins from proteomics (non-targeted) and from targeted inflammatory panels (cytokines/chemokines) differentiate CWP/FM from controls. The importance of proteins obtained from these two sources, the protein-protein association network, and the biological processes involved were investigated. Plasma proteins from women with CWP (n = 15) and CON (n = 23) were analyzed using two-dimensional gel electrophoresis analysis and a multiplex proximity extension assay for analysis of cytokines/chemokines. Associations between the proteins and group were multivarietly analyzed. The protein-protein association network and the biological processes according to the Gene Ontology were investigated. Proteins from both sources were important for group differentiation; the majority from the two-dimensional gel electrophoresis analysis. 58 proteins significantly differentiated the two groups (R2 = 0.83). A significantly enriched network was found; biological processes were acute phase response, complement activation, and innate immune response. As with other studies, this study shows that plasma proteins can differentiate CWP from healthy subjects. Focusing on cytokines/chemokines is not sufficient to grasp the peripheral biological processes that maintain CWP/FM since our results show that other components of the immune and inflammation systems are also highly significant.

Swedish Chronic Pain Biobank: protocol for a multicentre registry and biomarker project.

INTRODUCTION: About 20% of the adult population have chronic pain, often associated with psychological distress, sick leave and poor health. There are large variations in the clinical picture. A biopsychosocial approach is used in investigation and treatment. The concept of personalised medicine, that is, optimising medication types and dosages for individual patients based on biomarkers and other patient-related factors, has received increasing attention in different diseases but used less in chronic pain. This cooperative project from all Swedish University Hospitals will investigate whether there are changes in inflammation and metabolism patterns in saliva and blood in chronic pain patients and whether the changes correlate with clinical characteristics and rehabilitation outcomes. METHODS AND ANALYSIS: Patients at multidisciplinary pain centres at University Hospitals in Sweden who have chosen to participate in the Swedish Quality Registry for Pain Rehabilitation and healthy sex-matched and age-matched individuals will be included in the study. Saliva and blood samples will be collected in addition to questionnaire data obtained from the register. From the samples, proteins, lipids, metabolites and micro-RNA will be analysed in relation to, for example, diagnosis, pain characteristics, psychological distress, body weight, pharmacological treatment and clinical rehabilitation results using advanced multivariate data analysis and bioinformatics. ETHICS AND DISSEMINATION: The study is approved by the Swedish Ethical Review Authority (Dnr 2021-04929) and will be conducted in accordance with the declaration of Helsinki.The results will be published in open access scientific journals and in popular scientific relevant journals such as those from patient organisations. Data will be also presented in scientific meetings, meeting with healthcare organisations and disseminated in different lecturers at the clinics and universities.