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Abstract 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.

Abstract. Introduction:. Opioid treatment may affect endocrine measures in humans either through centrally or peripherally mediated mechanisms. There is a general lack of longitudinal studies examining endocrine measures in opioid-treated patients. Objectives:. To longitudinally follow the levels of select endocrine measures in men and women with head and neck cancer for 1 year, who after having completed radiotherapy began tapering opioids. Methods:. This was a prospective, longitudinal, observational study. Testosterone and estradiol were measured in men and women, respectively. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS), and prolactin were measured in both sexes. Women were grouped based on if premenopausal or postmenopausal. Samples were collected when opioid tapering started and at 1, 3, 6, and 12 months after tapering start. Daily opioid doses at the same time points were registered. Results:. Twenty-five men and 12 women were followed for 12 months. In men, testosterone levels increased significantly during the first month after opioid tapering started (P < 0.001). Levels of testosterone, FSH, DHEAS, and prolactin changed significantly in men during the study period. A moderate correlation between opioid dose reduction and testosterone level increase in men aged ≤60 years was found (rs = −0.577, 95% CI −0.854 to −0.044, P = 0.039). In postmenopausal women (n = 10), levels of FSH and LH changed significantly during the study period. Conclusion:. Previously known effects of opioids on endocrine measures in humans seem to be reversible as select endocrine measures changed significantly in men and postmenopausal women after opioid tapering was initiated.

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), mindfulness-based interventions (n = 5), and yoga (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.

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.

IntroductionTraditionally, 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.MethodsThe rationale for viewing cancer pain as a separate category is reviewed.ResultsCancer 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.ConclusionWithout 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).

Abstract 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.

In this paper, the question of theodicy is viewed from the perspective of time. It is argued that even a very shallow analysis reveals that the concept of “long time” is deeply anthropocentric. We do not know what time is to God, but it seems that the only reason why we call billions of years a long period is because we use ourselves as measuring rods. What if the time questions we ask in this context say more about our temporal smallness than about reality itself? Three possible objections are answered: 1) It is acknowledged that this is of course not meant to be a definite answer to the problem of evil. It is merely offered as a reframing that seems strangely absent from the discussion. 2) The question of pastoral relevance is briefly discussed. 3) The troubling problem of why God created sequentially over time and not “instantaneously” is explored. It is concluded that perhaps our appraisal of time might not be ontologically valid at all. This does not make suffering easy to bear, but perhaps thoughts like these can provide a little hope and endurance—at least for those of us who are philosophically and theologically inclined.

Abstract 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”).

Abstract 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.

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.

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

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.

Abstract Background The safety of sleeping pills has increased dramatically during the last 100 years, from barbiturates to bensodiazepines to modern day so-called Z-drugs. Methods The circumstances of prescribing sleeping pills in the early 20th century are illustrated by summarizing the main storyline of a novel by Swedish writer Vilhelm Moberg. This is followed by a thought experiment and a theoretical discussion. Results In his 1937 novel Sömnlös (Swedish for sleepless) Vilhelm Moberg portrayed existential and relational distress in relation to insomnia. In a thought experiment, past progresses in sleeping pills safety are projected into the future. Thereby, it is claimed that important issues in the area of philosophy of medicine come to the fore. This leads to a theoretical discussion about broader questions concerning the role of the physician, the goals of medicine (as described by Lennart Nordenfelt), the concept of pharmaceuticalisation (as described notably by sociologist of sleep Simon J. Williams and co-workers), and health enhancement (c.f. Carl Elliott and the alleged wish to be better than well). Conclusion Insomnia is a prism through which important philosophical and sociological questions related to the practice of medicine can be asked.

Abstract. Introduction:. Little is still known about the underlying mechanisms that drive and maintain neuropathic pain (NeuP). Recently, lipids have been implicated as endogenous proalgesic ligands affecting onset and maintenance of pain; however, in the case of NeuP, the relationship is largely unexplored. Objectives:. The aim of this study was to investigate the lipoprotein profile in patients with chronic peripheral NeuP compared with healthy controls. Methods:. The concentrations of 112 lipoprotein fractions in plasma from patients with NeuP (n = 16) and healthy controls (n = 13) were analyzed using proton nuclear magnetic resonance spectroscopy. A multiplex immunoassay based on an electrochemiluminescent detection method was used to measure the concentration of 71 cytokines in plasma from patients with NeuP (n = 10) and healthy controls (n = 11). Multivariate data analysis was used to identify patterns of protein intercorrelations and proteins significant for group discrimination. Results:. We found 23 lipoproteins that were significantly upregulated in patients with NeuP compared with healthy controls. When the influence of cytokines was included in a regression model, 30 proteins (8 cytokines and 22 lipoprotein fractions) were significantly upregulated or downregulated in patients with NeuP. Both conditions presented lipoprotein profiles consistent with inflammation. Body mass index did not affect lipoprotein profiles in either group. No relationship between age and lipoprotein pattern was found in NeuP, but a significant relationship was found in healthy controls. Conclusion:. Patients with NeuP presented a lipoprotein profile consistent with systemic low-grade inflammation, like that seen in autoimmune, cardiometabolic, and neuroprogressive diseases. These preliminary results emphasize the importance of chronic low-grade inflammation in NeuP.

Abstract Background Neuropathic pain (NeuP) is a complex, debilitating condition of the somatosensory system, where dysregulation between pro- and anti-inflammatory cytokines and chemokines are believed to play a pivotal role. As of date, there is no ubiquitously accepted diagnostic test for NeuP and current therapeutic interventions are lacking in efficacy. The aim of this study was to investigate the ability of three biofluids - saliva, plasma, and cerebrospinal fluid (CSF), to discriminate an inflammatory profile at a central, systemic, and peripheral level in NeuP patients compared to healthy controls. Methods The concentrations of 71 cytokines, chemokines and growth factors in saliva, plasma, and CSF samples from 13 patients with peripheral NeuP and 13 healthy controls were analyzed using a multiplex-immunoassay based on an electrochemiluminescent detection method. The NeuP patients were recruited from a clinical trial of intrathecal bolus injection of ziconotide (ClinicalTrials.gov identifier NCT01373983). Multivariate data analysis (principal component analysis and orthogonal partial least square regression) was used to identify proteins significant for group discrimination and protein correlation to pain intensity. Proteins with variable influence of projection (VIP) value higher than 1 (combined with the jack-knifed confidence intervals in the coefficients plot not including zero) were considered significant. Results We found 17 cytokines/chemokines that were significantly up- or down-regulated in NeuP patients compared to healthy controls. Of these 17 proteins, 8 were from saliva, 7 from plasma, and 2 from CSF samples. The correlation analysis showed that the most important proteins that correlated to pain intensity were found in plasma (VIP > 1). Conclusions Investigation of the inflammatory profile of NeuP showed that most of the significant proteins for group separation were found in the less invasive biofluids of saliva and plasma. Within the NeuP patient group it was also seen that proteins in plasma had the highest correlation to pain intensity. These preliminary results indicate a potential for further biomarker research in the more easily accessible biofluids of saliva and plasma for chronic peripheral neuropathic pain where a combination of YKL-40 and MIP-1α in saliva might be of special interest for future studies that also include other non-neuropathic pain states.

Objective: To explore the associations between habitual self-reported physical activity, pain sensitivity and patient-reported outcomes (including pain intensity) in patients with chronic pain. Design: Cross-sectional, experimental study. Subjects: Patients (n = 78), age range 18–65 years, with different chronic pain conditions (> 3 months) were compared with age- and sex-matched healthy controls (n = 98). Methods: Multivariate correlations between self-reported physical activity, pressure pain sensitivity, and patient-reported outcome measures were assessed. Results: Lower perceived health status (p < 0.001, Cohen’s d = 2.34), higher levels of depression (p < 0.001, Cohen’s d = 1.77), and lower pain tolerance threshold (p < 0.001, Cohen’s d = 1.66) were the most prominent variables discriminating patients from controls. In patients, bivariate and multivariate analyses showed that higher pressure pain tolerance was associated with male sex, lower pain intensity and fewer painful regions, higher self-efficacy and more self-reported physical activity, but not with lower levels of anxiety and depression. Conclusion: Pain tolerance thresholds, as well as degree of depression and perceived health status discriminated between patients and controls, and there was an association between pain tolerance thresholds and level of self-reported physical activity in patients. This study highlights the importance of further research into how increased physical activity may improve pain sensitivity in patients with chronic pain. LAY ABSTRACT Patients with chronic pain and healthy controls were included in this study of the relationships between self-reported physical activity, measurements of sensitivity to pressure pain, and questionnaire data. Pressure pain sensitivity was one of the most important factors discriminating between patients and controls, and there was a significant correlation between pain tolerance threshold and level of self-reported physical activity in patients (i.e. the lower pain thresholds the less physical activity). These results are relevant, as there are only a few previous studies examining the relationship between physical activity in patients with chronic pain and their sensitivity to pressure pain. More research is needed to explore how daily physical activity may improve chronic pain by, for example, increasing patient’s tolerance to pain.

Abstract Background Topical anaesthesia is important to optimize pain control during dental injection. Our aim was to describe a new simple method for topical anaesthesia of oral mucosa and to compare the effectiveness of ice and lidocaine 5% gel for topical anaesthesia of oral mucosa. Methods A total of 40 patients aged 10.7–19.5 years were included. The side and method of application were both randomized. Heart rate was recorded, and discomfort and pain were evaluated with a visual analogue scale (VAS). A paired t-test was used to compare mean values, a chi2 test was used to compare proportions, and a Pearson correlation test was used to examine correlations between variables. Results When ice was used, buccal injection VAS pain was rated lower (p = 0.044), and VAS discomfort was rated higher (p = 0.001), in comparison to when lidocaine 5% gel was used. There was no significant difference in relative heart rate change between ice and lidocaine 5% gel at either needle stick or injection. Lidocaine 5% gel produced a relative heart rate reduction after palatal injection (0.99 ± 0.06) while buccal injection produced an increased relative heart rate (1.02 ± 0.08) (p = 0.010). Unpleasant taste was more frequently reported when lidocaine 5% gel was used (p = 0.025). An application time of 1 min was sufficient for both ice and lidocaine 5% gel to achieve pain reduction from needle stick in buccal mucosa. Conclusion The cheap and readily available described method using ice for topical anaesthesia of oral mucosa before dental injection is an effective alternative to lidocaine 5% gel. Trial registration The European Union Drug Regulating Authorities Clinical Trials Database EudraCT201300530531. Date of registration: February 10th, 2014.

Background: The pathophysiology of fibromyalgia includes central and peripheral factors. Neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, are involved in peripheral and central nervous system development of pain and hyperalgesia. Few studies have examined circulating nerve growth factor and brain-derived neurotrophic factor in fibromyalgia or have investigated whether exercise interventions affect the levels of these peptides. Objectives: To compare plasma levels of nerve growth factor and brain-derived neurotrophic factor in fibromy-algia and in healthy controls, to investigate correlations between levels of nerve growth factor, brain-derived neurotrophic factor, and cytokines and clinical variables, and to investigate the effect of exercise on these levels. Subjects and methods: A total of 75 women with fibromyalgia participated in blood tests at baseline and after the 15-week intervention, and 25 healthy controls participated at baseline. Patients were randomized to a 15-week progressive resistance exercise intervention or a relaxation intervention. Results: Brain-derived neurotrophic factor level was significantly higher (p

Background: Chronic pain is prevalent in Sweden, nearing 20% in the adult population. Treatment often requires a multimodal approach, with medication, physical therapy and psychological interventions. However, the frequency of medication in patients with chronic pain in Sweden, and its correlation with patient-reported outcome measures (PROMs), are currently unknown. Objectives: To investigate the frequency of use of analgesics and other medication in patients with chro-nic pain referred to a multidisciplinary pain centre, and how opioid treatment relates to PROMs. Design: Cross-sectional, registry-based study. Patients: New referral visits (n = 1,275) to the Pain and Rehabilitation Center in Linköping, Sweden in 2015. 441 patients had complete medication and PROM data. Methods: Patient-reported analgesic and other medications were matched with patient PROM data from the Swedish Quality Registry for Pain Rehabilitation. Univariate analysis was conducted with IBM Statistical Package for the Social Sciences (SPSS; IBM Corporation, Somers, NY, USA) version 24.0, and multivariate analysis with SIMCA-P+ (version 13, Umetrics AB, Umeå, Sweden), with a special emphasis on opioids. Results: n = 132 (30%) patients used opioids daily, and this group differed from other patients on many PROMs, with medium effect sizes for pain severity, interference, health-related quality of life, activity engagement, and satisfaction with social life. Multivariate analysis identified four groups and showed that daily use of opioids was significantly correlated with high pain intensity and low physical functioning. Conclusion: Prevalence of daily opioid use was 30% and daily opioid use did not correlate with better outcome of PROMs. Longitudinal studies are warranted (e.g. on the clinical effect of tapering), as are studies that can better explain the medication variability in patients with complex chronic pain.

Abstract Background Post-translational modifications (PTMs) generate a tremendous protein diversity from the ~ 20,000 protein-coding genes of the human genome. In chronic pain conditions, exposure to pathological processes in the central nervous system could lead to disease-specific PTMs detectable in the cerebrospinal fluid (CSF). In a previous hypothesis-generating study, we reported that seven out of 260 CSF proteins highly discriminated between neuropathic pain patients and healthy controls: one isoform of angiotensinogen (AG), two isoforms of alpha-1-antitrypsin (AT), three isoforms of haptoglobin (HG), and one isoform of pigment epithelium-derived factor (PEDF). The present study had three aims: (1) To examine the multivariate inter-correlations between all identified isoforms of these seven proteins; (2) Based on the results of the first aim, to characterize PTMs in a subset of interesting proteins; (3) To regress clinical pain data using the 260 proteins as predictors, thereby testing the hypothesis that the above-mentioned seven discriminating proteins and/or the characterized isoforms/fragments of aim (2) would be among the proteins having the highest predictive power for clinical pain data. Methods CSF samples from 11 neuropathic pain patients and 11 healthy controls were used for biochemical analysis of protein isoforms. PTM characterization was performed using enzymatic reaction assay and mass spectrometry. Multivariate data analysis (principal component analysis and orthogonal partial least square regression) was applied on the quantified protein isoforms. Results We identified 5 isoforms of AG, 18 isoforms of AT, 5 isoforms of HG, and 5 isoforms of PEDF. Fragments and glycosylated isoforms of AT were studied in depth. When regressing the pain intensity data of patients, three isoforms of AT, two isoforms of PEDF, and one isoform of angiotensinogen “reappeared” as major results, i.e., they were major findings both when comparing patients with healthy controls and when regressing pain intensity in patients. Conclusions Altered levels of fragments and/or glycosylated isoforms of alpha-1-antitrypsin might mirror pathophysiological processes in the spinal cord of neuropathic pain patients. In particular, we suggest that a putative disease-specific combination of the levels of two different N-truncated fragments of alpha-1-antitrypsin might be interesting for future CSF and/or plasma biomarker investigations in chronic neuropathic pain.

Objective: The pathophysiology of chronic pain is complex, with most of our knowledge being derived from preclinical studies. The search for biomarkers mirroring the pathophysiology of chronic pain is ongoing, and there is an increasing interest in saliva as a diagnostic tool. Given what is known about salivary substance P and salivary gland innervation, we hypothesized that salivary substance P and/or beta-endorphin might reflect the basal activity of these neuropeptides in the central nervous system, thereby perhaps mirroring a general propensity to chronic pain. Based on this overall hypothesis, our aim was to compare salivary levels of these neuropeptides in chronic neuropathic pain patients with healthy controls. An additional aim was to relate salivary levels to plasma levels. Materials and methods: We compared salivary concentrations of beta-endorphin and substance P in 14 chronic neuropathic pain patients with concentrations in 18 healthy controls using a Luminex technology kit. Salivary-to-plasma quotients were also calculated. Results: We found no significant difference between the groups' salivary concentrations of substance P and beta-endorphin. No correlation was found between salivary and plasma concentrations of each neuropeptide, which we hypothesize might point to local production of beta-endorphin and/or substance P in the salivary glands. Given high substance P salivary-to-plasma quotients, such a local production seems more likely for substance P than for beta-endorphin. Conclusions: Propensity to neuropathic chronic pain was not substantiated by our analysis of salivary levels of substance P and/or beta-endorphin. However, we report salivary-to-plasma quotients that give potentially important physiological insight about these neuropeptides.

To subgroup chronic pain patients using psychometric data and regress the variables most responsible for subgroup discrimination.Cross-sectional, registry-based study.Chronic pain patients assessed at a multidisciplinary pain centre between 2008 and 2015.Data from the Swedish quality registry for pain rehabilitation (SQRP) were retrieved and analysed by principal component analysis, hierarchical clustering analysis, and partial least squares-discriminant analysis.Four subgroups were identified. Group 1 was characterized by low "psychological strain", the best relative situation concerning pain characteristics (intensity and spreading), the lowest frequency of fibromyalgia, as well as by a slightly older age. Group 2 was characterized by high "psychological strain" and by the most negative situation with respect to pain characteristics (intensity and spreading). Group 3 was characterized by high "social distress", the longest pain durations, and a statistically higher frequency of females. The frequency of three neuropathic pain conditions was generally lower in this group. Group 4 was characterized by high psychological strain, low "social distress", and high pain intensity.The identification of these four clusters of chronic pain patients could be useful for the development of personalized rehabilitation programs. For example, the identification of a subgroup characterized mainly by high perceived "social distress" raises the question of how to best design interventions for such patients. Differentiating between clinically important subgroups and comparing how these subgroups respond to interventions is arguably an important area for further research.

Chronic pain is highly prevalent, and pain medicine lacks objective biomarkers to guide diagnosis and choice of treatment. The current U.S. “opioid epidemic” is a reminder of the paucity of effective and safe treatment options. Traditional pain diagnoses according to the International Classification of Diseases are often unspecific, and analgesics are often prescribed on a trial-and-error basis. In contrast to this current state of affairs, the vision of future mechanism-based diagnoses of chronic pain conditions is presented in this non-technical paper, focusing on the need for biomarkers and the theoretical complexity of the task. Pain is and will remain a subjective experience, and as such is not objectively measurable. Therefore, the concept of “noci-marker” is presented as an alternative to “pain biomarker”, the goal being to find objective, measurable correlates of the pathophysiological processes involved in different chronic pain conditions. This vision entails a call for more translational pain research in order to bridge the gap between clinical pain medicine and preclinical science.