Tailored internet-based cognitive behavioral therapy for individuals with chronic pain and comorbid psychological distress: a randomized controlled trial.

Comorbid psychological problems are commonly related to chronic pain but addressing heterogeneous comorbidities in traditional settings is often difficult. Delivering individually tailored treatment using the internet could be a viable alternative. The present study investigates whether a guided, individually tailored and internet-delivered cognitive behavioral therapy (ICBT) could improve mood and reduce disability in individuals suffering from chronic pain and comorbid psychological distress.Participants were recruited from a pain clinic and randomized to either ICBT or waiting list. The participants (n = 187) individually tailored treatments included 6-13 modules targeting different types of psychological distress. Modules were designed to be completed weekly, and feedback was provided by clinicians. Participants completed an average of 5.1 (49.7%) modules, with 22.9% completing all assigned modules. Intention-to-treat analyses showed significantly larger improvements in depression, disability, pain acceptance, catastrophizing, and quality of life in the ICBT-group compared to the control group. Between-group effect sizes were very small or small at post for the primary outcomes depression (d = 0.18) and pain interference (d = 0.22). Other effect sizes ranged from very small to small, with the largest effect being improvements in pain acceptance (d = 0.3). All significant changes were stable at 12-month follow up.

Insomnia-related Memory Impairment in Individuals With Very Complex Chronic Pain.

OBJECTIVE: To investigate the specific effect of insomnia on neuropsychological functioning in patients with very complex chronic pain. BACKGROUND: Individuals with insomnia disorder or chronic pain often experience cognitive deficits, with both conditions appearing to correlate with impairments in neuropsychological functions. As insomnia often occurs comorbid with chronic pain, distinguishing the differential effects of these two syndromes on an individual's neuropsychological functioning can be challenging. Comorbid depressive symptoms in these individuals, which may also affect cognitive function, may further obscure the associations between chronic pain, insomnia, and the neuropsychological profile. METHODS: The neuropsychological function of 22 individuals with very complex chronic pain was assessed using specialized tests examining aspects of memory and executive functioning. The severity of insomnia, depression, and anxiety was measured using questionnaires, and pain levels were assessed using a visual analog scale. Pain medications were transformed to the morphine-equivalent daily dose. RESULTS: Insomnia severity was found to predict memory function, accounting for 32.4% of the variance: A 1 SD increase in insomnia severity decreased memory function by 0.57 SD. The negative correlation between insomnia and memory was significant even after controlling for pain level, morphine-equivalent daily dose, and comorbid levels of anxiety and depression. CONCLUSIONS: Insomnia severity independently predicted memory function in patients with very complex chronic pain, even after controlling for other factors known to impair cognitive function. Insomnia may possibly explain some of the cognitive impairments related to chronic pain; thus, screening for, and treating, sleep disturbances may be a central aspect of chronic pain rehabilitation.

Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period.

Paracetamol (acetaminophen) is a widely used non-prescription drug with analgesic and antipyretic properties. Among pregnant women and young children, paracetamol is one of the most frequently used drugs and is considered the first-choice treatment for pain and/or fever. Recent findings in both human and animal studies have shown associations between paracetamol intake during brain development and adverse behavioral outcomes later in life. The present study was undertaken to investigate if the induction of these effects depend on when the exposure occurs during a critical period of brain development and if male and female mice are equally affected. Mice of both sexes were exposed to two doses of paracetamol (30 + 30 mg kg-1 , 4 h apart) on postnatal days (PND) 3, 10 or 19. Spontaneous behavior, when introduced to a new home environment, was observed at the age of 2 months. We show that adverse effects on adult behavior and cognitive function occurred in both male and female mice exposed to paracetamol on PND 3 and 10, but not when exposed on PND 19. These neurodevelopmental time points in mice correspond to the beginning of the third trimester of pregnancy and the time around birth in humans, supporting existing human data. Considering that paracetamol is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for future research and, ultimately, for clinical practice. Copyright © 2017 John Wiley & Sons, Ltd.

Initial Sleep Time Predicts Success in Manual-Guided Cognitive Behavioral Therapy for Insomnia.

Cognitive behavioral therapy produces significant and long-lasting improvement for individuals with insomnia, but treatment resources are scarce. A "stepped care" approach has therefore been proposed, but knowledge is limited on how to best allocate patients to different treatment steps. In this study, 66 primary-care patients with insomnia attended a low-end treatment step: manual-guided cognitive behavioral therapy (CBT) for insomnia delivered by ordinary primary-care personnel. Based on clinically significant treatment effects, subjects were grouped into treatment responders or nonresponders. Baseline data were analyzed to identify predictors for treatment success. Long total sleep time at baseline assessment was the only statistically significant predictor for becoming a responder, and sleep time may thus be important to consider before enrolling patients in low-end treatments.

Spinal Cord Stimulation Alters Protein Levels in the Cerebrospinal Fluid of Neuropathic Pain Patients: A Proteomic Mass Spectrometric Analysis.

OBJECTIVES: Electrical neuromodulation by spinal cord stimulation (SCS) is a well-established method for treatment of neuropathic pain. However, the mechanism behind the pain relieving effect in patients remains largely unknown. In this study, we target the human cerebrospinal fluid (CSF) proteome, a little investigated aspect of SCS mechanism of action. METHODS: Two different proteomic mass spectrometry protocols were used to analyze the CSF of 14 SCS responsive neuropathic pain patients. Each patient acted as his or her own control and protein content was compared when the stimulator was turned off for 48 hours, and after the stimulator had been used as normal for three weeks. RESULTS: Eighty-six proteins were statistically significantly altered in the CSF of neuropathic pain patients using SCS, when comparing the stimulator off condition to the stimulator on condition. The top 12 of the altered proteins are involved in neuroprotection (clusterin, gelsolin, mimecan, angiotensinogen, secretogranin-1, amyloid beta A4 protein), synaptic plasticity/learning/memory (gelsolin, apolipoprotein C1, apolipoprotein E, contactin-1, neural cell adhesion molecule L1-like protein), nociceptive signaling (neurosecretory protein VGF), and immune regulation (dickkopf-related protein 3). CONCLUSION: Previously unknown effects of SCS on levels of proteins involved in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity are demonstrated. These findings, in the CSF of neuropathic pain patients, expand the picture of SCS effects on the neurochemical environment of the human spinal cord. An improved understanding of SCS mechanism may lead to new tracks of investigation and improved treatment strategies for neuropathic pain.

The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid.

Cytokines and chemokines regulate many functions in the body including the brain. The interactions between adipose tissue and the central nervous system (CNS) are important for the regulation of energy balance. CNS function is also influenced by age. The aim of the present study was to investigate the effects of body mass index (BMI) and age on cytokine and chemokine levels in cerebrospinal fluid. Cerebrospinal fluid samples (n=89) were collected from patients undergoing routine surgical procedures. The samples were analyzed using the multiplex proximity extension assay (PEA) in which 92 different cytokines are measured simultaneously using minute sample volume. We found no significant correlations between age and cytokine levels for any of the studied markers. In contrast, at a false discovery rate of 10%, 19 markers were significantly associated with BMI (in decreasing significance: FGF-5, ADA, Beta-NGF, CD40, IL-10RB, CCL19, TGF-alpha, SIRT2, TWEAK, SCF, CSF-1, 4E-BP1, DNER, LIF-R, STAMPB, CXCL10, CXCL6, VEGF-A and CX3CL1). This study reveals a clear effect of BMI on cytokine and chemokine levels in cerebrospinal fluid.

Increased risk of persistent neuropathic pain after traumatic nerve injury and surgery for carriers of a human leukocyte antigen haplotype.

ABSTRACT: It is not known why some patients develop persistent pain after nerve trauma while others do not. Among multiple risk factors for the development of persistent posttrauma and postsurgical pain, a neuropathic mechanism due to iatrogenic nerve lesion has been proposed as the major cause of these conditions. Because there is some evidence that the human leukocyte antigen (HLA) system plays a role in persistent postsurgical pain, this study aimed to identify the genetic risk factors, specifically among HLA loci, associated with chronic neuropathic pain after traumatic nerve injuries and surgery in the upper extremities. Blood samples were taken to investigate the contribution of HLA alleles (ie, HLA-A, HLA-B, HLA-DRB1, HLA-DQB1, and HLA-DPB1) in a group of patients with persistent neuropathic pain (n = 70) and a group of patients with neuropathy without pain (n = 61). All subjects had intraoperatively verified nerve damage in the upper extremity. They underwent bedside clinical neurological examination to identify the neuropathic pain component according to the present grading system of neuropathic pain. Statistical analyses on the allele and haplotype were conducted using the BIGDAWG package. We found that the HLA haplotype A*02:01-B*15:01-C*03:04-DRB1*04:01-DQB1*03:02 was associated with an increased risk of developing persistent neuropathic pain in the upper extremity (OR = 9.31 [95% CI 1.28-406.45], P < 0.05). No significant associations were found on an allele level when correcting for multiple testing. Further studies are needed to investigate whether this association is on a haplotypic level or if certain alleles may be causing the association.

Intravenous S-ketamine's analgesic efficacy in third molar surgery. A randomized placebo-controlled double-blind clinical trial.

Background: In most cases, a combination of paracetamol and ibuprofen are the optimal treatment for postoperative pain in third molar surgery. If stronger analgesia is required, opioids are traditionally administered. In day-case, surgery; however, opioids should be avoided. Thus, the anaesthetic agent S-ketamine in analgesic doses might be preferred. Methods: The study was designed as a randomized placebo-controlled double-blind clinical trial. The study enrolled healthy subjects according to the American Society of Anaesthesiologists classification; I or II (ASA), aged 18 to 44 years, with a body weight between 50 and 100 kg. The patients were randomized into three groups where two doses of S-ketamine were compared (high: 0.25 mg/kg or low: 0.125 mg/kg) with placebo (saline). Results: A primary outcome of the study was that VAS at 4 h postoperatively, showed no significant difference between the placebo and high-dose S-ketamine group or in the low-dose group. We found a significant difference between the groups for the first 24 h, with a lower VAS-score in the high-dose S-ketamine group. The time to when 50% had taken their first rescue medication was 12 min later in the high-dose ketamine group. Conclusions: Pre-emptive S-ketamine 0.25 mg/kg gave a global significant reduction of pain by VAS during the first 24 h postoperatively. The time from end of surgery to first rescue medication were longer in the high-dose ketamine group compared to both low-dose ketamine and placebo groups.

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.

Cerebrospinal fluid cathepsin B and S.

Cathepsins are increased in the brain of elderly animals. We investigate the presence of cathepsin B and S in human cerebrospinal fluid (CSF) plasma and the associations with cystatin C, age and sex. We measured cathepsin B and S concentrations in CSFs from 118 persons, undergoing elective surgical procedures, with ELISA. Both cathepsin B and cathepsin S were positively correlated with age. No correlation was observed between cathepsin B or S and length, height or body mass index. Both cathepsin B and S were positively correlated to the cystatin C concentration in CSF. Calculated reference intervals were 4,893-17,636 pg/mL for cathepsin B and 2,681-11,459 pg/mL for cathepsin S. Elderly individuals had significantly higher levels of both cathepsin B (r s = 0.38, p = 0.00002) and cathepsin S (r s = 0.35, p = 0.0001) in CSF.

Targeting oxidative injury and cytokines' activity in the treatment with anti-tumor necrosis factor-α antibody for complex regional pain syndrome 1.

Cytokines and oxygen free radicals have been implicated in the potential pathogenic development of complex regional pain syndrome (CRPS). We aimed to analyze the relationship between clinical status, circulating levels of cytokines, and markers of oxidative damage during the treatment with anti-TNFα antibodies. The patient chosen for treatment had not had improvement through a number of conventional therapies and fulfilled the current diagnostic criteria for CRPS-1. We investigated the clinical variables before and after systemic administration of 1.4 mg/kg anti-TNFα antibody (infliximab), repeated after 1 month in a dose of 3 mg/kg. Blood samples were collected before and after anti-TNFα antibodies administration, and plasma was analyzed for 8-isoprostane-prostaglandin F2α (8-iso-PGF2α, a marker of oxidative injury) and cytokines (TNF-α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-17A). Plasma concentrations of 8-iso-PGF2α were measured with radioimmunoassay (RIA), and the kinetics of cytokines were detected in plasma by antibody-based proximity ligation (PLA). Pathologically high levels of 8-iso-PGF2α were found in the patient. Immediately after each administration of infliximab, the levels of 8-iso-PGF2α decreased. Although the patient showed an improvement of the cutaneous dystrophic symptoms and diminished pain associated with these lesions, the levels of circulating TNFα increased after the administration of anti-TNFα antibodies. In a patient with CRPS-1 treated with anti-TNFα antibodies, we report increased levels of circulating TNFα and a temporary mitigation of oxidative stress as measured by plasma F2 -isoprostane. This case report provides evidence 2 supporting the indication of monitoring the oxidative stress biomarkers during treatment with anti-TNFα antibodies in CRPS 1.

Association between systemic inflammation and experimental pain sensitivity in subjects with pain and painless neuropathy after traumatic nerve injuries.

OBJECTIVES: Peripheral neuropathies that occur secondary to nerve injuries may be painful or painless, and including a low-grade inflammation and pro-inflammatory cytokines associated with both regeneration and damage of peripheral nerve cells and fibers. Currently, there are no validated methods that can distinguished between neuropathic pain and painless neuropathy. The aim of this study was to search for proinflammatory and anti-inflammatory proteins associated with pain and experimental pain sensitivity in subjects with surgeon-verified nerve injuries in the upper extremities. METHODS: One hundred and thirty-one subjects [69 with neuropathic pain, NP; 62 with painless neuropathy, nP] underwent a conditioned pain modulation (CPM) test that included a cold pressor task (CPT) conducted with the non-injured hand submerged in cold water (4 °C) until pain was intolerable. CPM was assessed by pain ratings to pressure stimuli before and after applying the CPT. Efficient CPM effect was defined as the ability of the individual's CS to inhibit at least 29% of pain (eCPM). The subjects were assigned to one of two subgroups: pain sensitive (PS) and pain tolerant (PT) after the time they could tolerate their hand in cold water (PS<40 s and PT=60 s) . Plasma samples were analyzed for 92 proteins incorporated in the inflammation panel using multiplex Protein Extension Array Technology (PEA). Differentially expressed proteins were investigated using both univariate and multivariate analysis (principal component analysis-PCA and orthogonal partial least-squares discriminant analysis-OPLS-DA). RESULTS: Significant differences in all protein levels were found between PS and PT subgroups (CV-ANOVA p<0.001), but not between NP and nP groups (p=0.09) or between inefficient CPM (iCPM) and eCPM (p=0.53) subgroups. Several top proteins associated with NP could be detected using multivariate regression analysis such as stromelysin 2 (MMPs), interleukin-2 receptor subunit beta (IL2RB), chemokine (C-X-C motif) ligand 3 (CXCL3), fibroblast growth factor 5 (FGF5), chemokine (C-C motif) ligand 28 (CCL28), CCL25, CCL11, hepatocyte growth factor (HGF), interleukin 4 (IL4), IL13. After adjusting for multiple testing, none of these proteins correlated significantly with pain. Higher levels of CCL20 (p=0.049) and CUB domain-containing protein (CDCP-1; p=0.047) were found to correlate significantly with cold pain sensitivity. CDCP-1 was highly associated with both PS and iCPM (p=0.042). CONCLUSIONS: No significant alterations in systemic proteins were found comparing subjects with neuropathic pain and painless neuropathy. An expression of predominant proinflammatory proteins was associated with experimental cold pain sensitivity in both subjects with pain and painless neuropathy. One these proteins, CDC-1 acted as "molecular fingerprint" overlapping both CPM and CPT. This observation might have implications for the study of pain in general and should be addressed in more detail in future experiments.

Patients' experiences of treatment-relevant processes in multimodal pain rehabilitation for severe complex regional pain syndrome - a qualitative study.

PURPOSE: Complex regional pain syndrome (CRPS) is a longstanding condition with spontaneous and evoked pain, that usually occurs in an upper or lower extremity. Although it often resolves within the first year, it may for a minority progress to a chronic and occasionally severely disabling condition. The aim of this study was to explore patients' experiences and perceived effects of a specific treatment, designed for patients with severe and highly disabling CRPS, in order to identify possible treatment-relevant processes. METHODS: The method used was a qualitative design, using semi-structured interviews with open-ended questions to capture participants' experiences and perceptions. Ten interviews were analyzed using applied thematic analysis. RESULTS: Despite the fact that participants had a severe conditions, including nerve damage and a long duration of illness, they reported having been helped to increase flexible persistence, reduce fear and avoidance, and improve connections. This helped participants to significant improvements in daily life functioning. CONCLUSIONS: The participants described distinct possible treatment-relevant processes leading to a substantial improvement in everyday life. The results imply that there is hope for this group that has been severely disabled for many years. This may help guide future clinical treatment trials.

Flexible persistence, i.e., to lead a life more in line with personal values, despite pain and limitations, seems to be an important theme in the treatment for complex regional pain syndrome (CRPS).Acceptance-based exposure treatment can be helpful in reducing fear and avoidance behaviors.Both improved social connections and increased self-connection may be highly valuable in CRPS rehabilitation.

Sex-related differences in experimental pain sensitivity in subjects with painful or painless neuropathy after surgical repair of traumatic nerve injuries.

Introduction: Sex-related influences represent a contributor to greater pain sensitivity and have a higher prevalence of many chronic pain conditions, including neuropathic pain (NP), among women. Objectives: The aim was to analyze how differences in ongoing pain, experimental pain intensity, and conditioned pain modulation (CPM) relate to sex in subjects with neuropathy after traumatic nerve injuries. Methods: Endogenous pain modulation was compared between male (n = 77) and female (n = 55) subjects and between subjects with NP (female = 31, male = 39) and pain-free subjects with posttraumatic neuropathy (female = 24, male = 38). Conditioned pain modulation was assessed by pain ratings to pressure stimuli before and after a noxious conditioning stimulus (CS) conducted with one arm submerged in cold water (4°C) for 1 minute. Time of recovery (Time off) of pain intensity from peak VASmaxc after CS was recorded and compared between male and female patients. Results: Greater ongoing pain intensity was found among female patients compared with male patients and more experimental pain after pressure and cold induced pain. Summing all groups together, women had 0.8 times higher odds (20%) of recovering sooner than men after CS (95% CI = 0.65-2.9). No differences in CPM, time off, and psychosocial variables were seen between female and male patients (P < 0.05). Conclusion: Our hypothesis for sex differences in endogenous pain modulation was only supported by a shorter after-sensation time after cold CS in female patients. No sex differences in the magnitude of CPM effect were identified. Increased pain intensity for experimental pain, in both neuropathic pain and neuropathy without pain, was found in female patients.

Cerebrospinal Fluid in Classical Trigeminal Neuralgia: An Exploratory Study on Candidate Biomarkers.

Trigeminal neuralgia (TN) is a severe type of facial pain. A neurovascular conflict between cranial nerve V and a nearby vessel is the main pathophysiological mechanism, but additional factors are likely necessary to elicit TN. In this study, the primary aim was to explore differences in protein expression in the cerebrospinal fluid (CSF) of TN patients in relation to controls. Methods: Sixteen TN patients treated with microvascular decompression and 16 control patients undergoing spinal anesthesia for urological conditions were included. Lumbar CSF was collected preoperatively for the TN patients and before spinal anesthesia for the controls. A multiplexed proximity extension analysis of 91 CSF proteins was conducted using Proseek Multiplex Development 96, including biomarkers of cell communication, cell death, neurogenesis, and inflammation Results: The TN patients and the controls were of similar age, sex, and burden of co-morbidities. The TN patients exhibited higher concentrations of Clec11a, LGMN, MFG-E8, and ANGPTL-4 in CSF than the controls (q < 0.05). Conclusions: TN patients exhibited increased CSF biomarkers indicative of peripheral demyelinating injury (Clec11a), immune tolerance and destruction of myelin (LGMN), neuronal cell death (MFG-E8), and disturbances in myelin clearance (ANGPTL-8). Our findings are hypothesis-generating for candidate biomarkers and pathophysiological processes in classical TN.

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.

Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl positron emission tomography and computed tomography.

ABSTRACT: Knowledge of etiological mechanisms underlying whiplash-associated disorders is incomplete. Localisation and quantification of peripheral musculoskeletal injury and inflammation in whiplash-associated disorders would facilitate diagnosis, strengthen patients' subjective pain reports, and aid clinical decisions, all of which could lead to improved treatment. In this longitudinal observational study, we evaluated combined [11C]-D-deprenyl positron emission tomography and computed tomography after acute whiplash injury and at 6-month follow-up. Sixteen adult patients (mean age 33 years) with whiplash injury grade II were recruited at the emergency department. [11C]-D-deprenyl positron emission tomography and computed tomography, subjective pain levels, self-rated neck disability, and active cervical range of motion were recorded within 7 days after injury and again at 6-month follow-up. Imaging results showed possible tissue injuries after acute whiplash with an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints, associated with subjective pain locale and levels, as well as self-rated disability. At follow-up, some patients had recovered and some showed persistent symptoms and reductions in [11C]-D-deprenyl uptake correlated to reductions in pain levels. These findings help identify affected peripheral structures in whiplash injury and strengthen the idea that positron emission tomography and computed tomography detectable organic lesions in peripheral tissue are relevant for the development of persistent pain and disability in whiplash injury.

Hepatocyte growth factor, colony-stimulating factor 1, CD40, and 11 other inflammation-related proteins are associated with pain in diabetic neuropathy: exploration and replication serum data from the Pain in Neuropathy Study.

ABSTRACT: One in 5 patients with diabetes suffers from chronic pain with neuropathic characteristics, but the pathophysiological mechanisms underlying the development of neuropathic pain in patients with diabetic distal symmetrical polyneuropathy (DSP) are poorly understood. Systemic low-grade inflammation has been implicated, but there is still a considerable knowledge gap concerning its scope and meaning in this context. The aim of the study was to establish the broad inflammatory signature of painful diabetic DSP in serum samples from the Pain in Neuropathy Study, an observational cross-sectional multicentre study in which participants underwent deep phenotyping. In the present two cohorts exploration-replication study (180 participants in each cohort), serum samples from Pain in Neuropathy Study participants were analyzed with the Olink INFLAMMATION panel (Olink Bioscience, Uppsala, Sweden) that enables the simultaneous measurement of 92 inflammation-related proteins (mainly cytokines, chemokines, and growth factors). In both the exploration and the replication cohort, we identified a high-inflammation subgroup where 14 inflammation-related proteins in particular were associated with more neuropathy and higher pain intensity. The top 3 proteins were hepatocyte growth factor, colony-stimulating factor 1, and CD40 in both cohorts. In the exploratory cohort, additional clinical data were available, showing an association of inflammation with insomnia and self-reported psychological distress. Hence, this cross-sectional exploration-replication study seems to confirm that low-grade systemic inflammation is related to the severity of neuropathy and neuropathic pain in a subgroup of patients with diabetic DSP. The pathophysiological relevance of these proteins for the development of neuropathic pain in patients with diabetic DSP must be explored in more depth in future studies.

Why is pain still not being assessed adequately? Results of a pain prevalence study in a university hospital in Sweden.

AIM: The aim of this study was to investigate the prevalence of pain and pain assessment among inpatients in a university hospital. BACKGROUND: Pain management could be considered an indicator of quality of care. Few studies report on prevalence measures including all inpatients. DESIGN: Quantitative and explorative. METHOD: Survey. RESULTS: Of the inpatients at the hospital who answered the survey, 494 (65%) reported having experienced pain during the preceding 24 hours. Of the patients who reported having experienced pain during the preceding 24 hours, 81% rated their pain >3 and 42.1% rated their pain >7. Of the patients who reported having experienced pain during the preceding 24 hours, 38.7% had been asked to self-assess their pain using a Numeric Rating Scale (NRS); 29.6% of the patients were completely satisfied, and 11.5% were not at all satisfied with their participation in pain management. CONCLUSIONS: The result showed that too many patients are still suffering from pain and that the NRS is not used to the extent it should be. Efforts to overcome under-implementation of pain assessment are required, particularly on wards where pain is not obvious, e.g., wards that do not deal with surgery patients. Work to improve pain management must be carried out through collaboration across professional groups. RELEVANCE TO CLINICAL PRACTICE: Using a pain assessment tool such as the NRS could help patients express their pain and improve communication between nurses and patients in relation to pain as well as allow patients to participate in their own care. Carrying out prevalence pain measures similar to those used here could be helpful in performing quality improvement work in the area of pain management.

Thermal Pain Thresholds Are Significantly Associated with Plasma Proteins of the Immune System in Chronic Widespread Pain-An Exploratory Pilot Study Using Multivariate and Network Analyses.

Chronic widespread pain (CWP), including fibromyalgia (FM), is characterized by generalized musculoskeletal pain. An important clinical feature is widespread increased pain sensitivity such as lowered pain thresholds for different stimuli such as heat (HPT) and cold (CPT). There is a growing interest in investigating the activated neurobiological mechanisms in CWP. This explorative proteomic study investigates the multivariate correlation pattern between plasma and muscle proteins and thermal pain thresholds in CWP and in healthy controls (CON). In addition, we analysed whether the important proteins and their networks for CPT and HPT differed between CWP and CON. We used a proteomic approach and analysed plasma and muscle proteins from women with CWP (n = 15) and CON (n = 23). The associations between the proteins and CPT/HPT were analysed using orthogonal partial least square (OPLS). The protein-protein association networks for the important proteins for the two thermal pain thresholds were analysed using STRING database. CWP had lowered pain thresholds for thermal stimulus. These levels were generally not related to the included clinical variables except in CWP for HPT. Highly interacting proteins mainly from plasma showed strong significant associations with CPT and HPT both in CWP and in CON. Marked differences in the important proteins for the two thermal pain thresholds were noted between CWP and CON; more complex patterns emerged in CWP. The important proteins were part of the immune system (acute phase proteins, complement factors, and immunoglobulin factors) or known to interact with the immune system. As expected, CWP had lowered pain thresholds for thermal stimulus. Although different proteins were important in the two groups, there were similarities. For example, proteins related to the host defence/immunity such as acute phase proteins, complement factors, immunoglobulin factors, and cytokines/chemokines (although not in CON for CPT) were important habitual/tonic factors for thermal pain thresholds. The fact that peripheral proteins contribute to thermal pain thresholds does not exclude that central factors also contribute and that complex interactions between peripheral and central factors determine the registered pain thresholds in CWP.