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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Prolonged time of after-sensation after experimental pain stimuli despite efficient conditioned pain modulation in patients with chronic neuropathic pain after traumatic nerve injuries in upper extremity.

BACKGROUND: As yet, there is limited research that can identify factors that differentiate between painful and nonpainful neuropathies after traumatic nerve injury. The aim of this study was to compare subjects with pain and without pain, all after operative nerve repair in the upper extremities. METHODS: Subjects in both groups (pain, n = 69; painless, n = 62) underwent clinical assessment of sensory nerve function and psychophysical tests: quantitative sensory testing and conditioned pain modulation (CPM). Conditioned pain modulation was assessed by pain ratings to 120 seconds pressure stimuli administered before and after a 60 seconds noxious 4°C cold conditioning stimulus (CS). Time of recovery (time off) of pain intensity from peak VASmaxc after CS was recorded. Questionnaires about the quality of life (RAND-36) and disability of the extremity (QuickDash) were completed. RESULTS: There were no significant differences between groups for CPM (P = 0.19). Time off was 42 seconds in subjects with pain in comparison with 28 seconds in those without pain (P < 0.0001). Compared with individuals reporting no pain, participants with neuropathic pain after nerve injuries had 1.8 times the odds of recovering later after CS, gain of function findings at sensory examination (P < 0.0001), lower scores of the physical component of RAND-36 (P < 0.0001), and increase arm disability (P < 0.0001). Hyperesthesia to cold pain stimulation (P = 0.03) and lowered pain pressure threshold (P = 0.01) were found in the pain group. CONCLUSION: Recovery after the pain induced by cold CS indicates changes in central processing of pain and provides a potential measurement of endogenous pain modulation in individuals with chronic neuropathic pain.

Increased CSF Levels of Apolipoproteins and Complement Factors in Trigeminal Neuralgia Patients-In Depth Proteomic Analysis Using Mass Spectrometry.

The main cause of trigeminal neuralgia (TN) is compression of a blood vessel at the root entry zone of the trigeminal nerve. However, a neurovascular conflict does not seem to be the only etiology and other mechanisms are implicated in the development of the disease. We hypothesized that TN patients may have distinct protein expression in the CSF. In this study, lumbar CSF from TN patients (n = 17), scheduled to undergo microvascular decompression, and from controls (n = 20) was analyzed and compared with in depth mass spectrometry TMTbased quantitative proteomics. We identified 2552 unique proteins, of which 46 were significantly altered (26 increased, and 20 decreased, q-value < .05) in TN patients compared with controls. An over-representation analysis showed proteins involved in high-density lipoprotein, such as Apolipoprotein A4, Apolipoprotein M, and Apolipoprotein A1, and the extracellular region, including proteins involved in the complement cascade to be over-represented. We conclude that TN patients have distinct protein expression in the CSF compared to controls. The pathophysiological background of the protein alterations found in this study warrants further investigation in future studies. PERSPECTIVE: In this article, cerebrospinal fluid from patients with trigeminal neuralgia was analyzed using in depth shotgun proteomics, revealing 46 differentially expressed proteins compared to controls. Among these, apolipoproteins and proteins involved in the complement system were elevated and significantly over-represented, implying an inflammatory component in the pathophysiology of the disease.

A population-based study of inflammatory mechanisms and pain sensitivity.

Two recent studies suggest that experimental pain sensitivity is associated with low-grade systemic inflammation. However, only 2 biomarkers have been identified, and the studies were conducted in adult individuals where confounding effects of comorbid diseases cannot be excluded. We therefore tested associations between pain sensitivity and 119 inflammation-related serum biomarkers in 827 healthy adolescents (15-19 years) in the population-based Tromsø Study: Fit Futures. The main outcome measure was cold-pressor pain tolerance (CPT), tested by placing the dominant hand in circulating cold (3°C) water for a maximum of 105 seconds. Secondary outcomes were heat and pressure pain threshold and tolerance. Twelve proteins and 6 fatty acids were significantly associated with CPT after adjustment for possible confounding factors and correction for multiple comparisons. Of these, all fatty acids and 10 proteins were protective, ie, higher biomarkers levels were associated with increased CPT, whereas 2 biomarkers were associated with lower tolerance. Taken together, these biomarkers predicted completion of the tolerance test with a C-statistic of 0.65. Results for heat and pressure pain tolerance were remarkably similar, strengthening the generalizability of our findings. In this cohort of young healthy individuals, we found a relationship between inflammation-related biomarkers and pain tolerance and thresholds. Biomarkers with anti-inflammatory and analgesic effects predominated, suggesting that the development of prophylactic dietary or pharmaceutical treatments may be possible.

CSF levels of apolipoprotein C1 and autotaxin found to associate with neuropathic pain and fibromyalgia.

OBJECTIVE: Neuropathic pain and fibromyalgia are two common and poorly understood chronic pain conditions that lack satisfactory treatments, cause substantial suffering and societal costs. Today, there are no biological markers on which to base chronic pain diagnoses, treatment choices or to understand the pathophysiology of pain for the individual patient. This study aimed to investigate cerebrospinal fluid (CSF) protein profiles potentially associated with fibromyalgia and neuropathic pain. METHODS: CSF samples were collected from 25 patients with neuropathic pain (two independent sets, n=14 patients for discovery, and n=11 for verification), 40 patients with fibromyalgia and 134 controls without neurological disease from two different populations. CSF protein profiling of 55 proteins was performed using antibody suspension bead array technology. RESULTS: We found increased levels of apolipoprotein C1 (APOC1) in CSF of neuropathic pain patients compared to controls and there was a trend for increased levels also in fibromyalgia patients. In addition, levels of ectonucleotide pyrophosphatase family member 2 (ENPP2, also referred to as autotaxin) were increased in the CSF of fibromyalgia patients compared to all other groups including patients with neuropathic pain. CONCLUSION: The increased levels of APOC1 and ENPP2 found in neuropathic pain and fibromyalgia patients may shed light on the underlying mechanisms of these conditions. Further investigation is required to elucidate their role in maintaining pain and other main symptoms of these disorders.

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.

Chronic neuropathic pain after traumatic peripheral nerve injuries in the upper extremity: prevalence, demographic and surgical determinants, impact on health and on pain medication.

Background and aims Aside from the long term side effects of a nerve injury in the upper extremity with devastating consequences there is often the problem of chronic neuropathic pain. The studies concerning the prevalence of persistent pain of neuropathic origin after peripheral nerve injuries are sparse. The prevalence and risk factors associated with chronic neuropathic pain after nerve injuries in the upper extremity were assessed. Methods A standardized data collection template was employed prospectively and retrospectively for all patients with traumatic nerve injuries accepted at the Hand Surgery Department, Uppsala, Sweden between 2010 and 2018. The template included demographic data, pain diagnosis, type of injured nerve, level of injury, date of the lesion and repair, type of procedure, reoperation, time since the procedure, S-LANSS questionnaire (Self report-Leeds Assessment of Neuropathic Symptoms and Signs), RAND-36 (Item short form health survey), QuickDASH (Disability of Shoulder, Arm and Hand) and additional questionnaires concerned medication, pain intensity were sent to 1,051 patients with nerve injuries. Partial proportional odds models were used to investigate the association between persistent pain and potential predictors. Results More than half of the patients undergoing a surgical procedure developed persistent pain. Prevalence of neuropathic pain was 73% of the patients with pain (S-LANSS ≥ 12 or more). Multivariate analysis indicated that injury of a major nerve OR 1.6 (p = 0.013), years from surgery OR 0.91 (p = 0.01), younger age OR 0.7 (p < 0.001), were the main factors for predicting pain after surgery. The type of the nerve injured was the strongest predictor for chronic pain with major nerves associated with more pain (p = 0.019). Conclusions A high prevalence of chronic pain and neuropathic pain with a negative impact on quality of life and disability were found in patients after traumatic nerve injury. Major nerve injury, younger age and less time from surgery were predictors for chronic pain.

Cerebrospinal fluid biomarkers of inflammation in trigeminal neuralgia patients operated with microvascular decompression.

Compression of the trigeminal root entry zone by a blood vessel can cause trigeminal neuralgia (TN). However, a neurovascular conflict does not explain all cases of TN, and TN can exist without a neurovascular contact. A common observation during microvascular decompression surgery to treat TN is arachnoiditis in the region of the trigeminal nerve. Thus, aberrant inflammatory mechanisms may be involved in the pathophysiology of TN but information about the role of inflammation in TN is scarce. We used Proximity Extension Assay technology to analyse the levels of 92 protein biomarkers related to inflammation in lumbar cerebrospinal fluid from patients with TN (n = 27) before and after microvascular decompression compared to individuals without TN. We aimed to analyse the pattern of inflammation-related proteins in order to improve our understanding of the pathophysiology of TN. The main finding was that immunological protein levels in the cerebrospinal fluid from patients with TN decreased after surgery towards levels observed in healthy controls. Two proteins seemed to be of specific interest for TN: TRAIL and TNF-ß. Thus, inflammatory activity might be one important mechanism in TN.

Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease.

BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases. METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease. RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL. CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.