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Background and aims Recent research indicates a previously unknown low-grade systemic or neurogenic inflammation in groups of chronic pain (CP) patients. Low-grade inflammation may have an important role in symptoms that have previously not been well depicted: widespread pain, tiredness and cognitive dysfunctions frequently seen in severely impaired CP patients. This study aimed to investigate the plasma inflammatory profile in a group of very complex CP patients at baseline and at a 1-year follow-up after participation in a cognitive behavior therapy (CBT)-based multimodal pain rehabilitation program (PRP). Methods Blood samples were collected from 52 well-characterized CP patients. Age- and sex-matched healthy blood donors served as controls. The samples were analyzed with a multiple Proximal Extension Analysis allowing a simultaneous analysis of 92 inflammation-related proteins consisting mainly of cytokines, chemokines and growth-factors. At follow-up, 1-year after participation in the RPR samples from 28 patients were analyzed. The results were confirmed by a multi-array technology that allows quantitative estimation. Results Clear signs of increased inflammatory activity were detected in the CP patients. Accepting a false discovery rate (FDR) of 5%, there were significant differences in 43/92 inflammatory biomarkers compared with the controls. In three biomarkers (CXCL5, SIRT2, AXIN1) the expression levels were elevated more than eight times. One year after the PRP, with the patients serving as their own controls, a significant decrease in overall inflammatory activity was found. Conclusions Our results indicate that the most impaired CP patients suffer from low-grade chronic systemic inflammation not described earlier with this level of detail. The results may have implications for a better understanding of the cluster of co-morbid symptoms described as the "sickness-syndrome" and the wide-spread pain seen in this group of patients. The decrease in inflammatory biomarkers noted at the follow-up after participation in the PRP may reflect the positive effects obtained on somatic and psycho-social mechanisms involved in the inflammatory process by a rehabilitation program. Besides the PRP, no major changes in medication or lifestyle factors were implemented during the same period. To our knowledge, this is the first study reporting that a PRP may induce inflammatory-reducing effects. Further studies are needed to verify the objective findings in CP patients and address the question of causality that remains to be solved. Implications The findings offer a new insight into the complicated biological processes underlying CP. It may have implications for the understanding of symptoms collectively described as the "sickness-syndrome" – frequently seen in this group of patients. The lowering of cytokines after the participation in a PRP indicate a new way to evaluate this treatment; by measuring inflammatory biomarkers.
Learn More >Itch consists of both sensory and affective components. For chronic itch patients, the affective component of itch affects both quality of life (leading to psychological comorbidities) and disease prognosis (by promoting scratching of itchy skin). We found that acute itch stimuli such as histamine induced anxiety-like behavior and increased activity (c-Fos expression) in the amygdala in adult male C57BL/6 mice. Itch stimuli also increased activity in projection areas to the amygdala, suggesting that these regions form a circuit for affective itch processing. Electrophysiological characterization of histamine-responsive amygdala neurons showed that this population was active on a behaviorally relevant timescale and partially overlapped with pain signaling. Selective optogenetic activation of histamine-responsive amygdala neurons in adult male and female Fos:CreER;R26 mice using the Targeted Recombination in Active Populations system enhanced both scratching and anxiety-like behavior. These results highlight the importance of itch-responsive amygdala neurons in modulating itch-related affect and behavior.The sensation of itch includes an affective component that leads to stress and anxiety in chronic itch patients. We investigated the neuronal basis of affective itch in mice, with a focus on the amygdala, the key brain region for the generation of anxiety. A subpopulation of amygdala neurons responded to itch stimuli such as histamine. Optogenetic activation of histamine-responsive amygdala neurons affected both scratching and anxiety-like behavior. Therefore, this population appears to be important for mediating the affective component of itch.
Learn More >Background and aims Complex Regional Pain Syndrome (CRPS) often recovers spontaneously within the first year, but when it becomes chronic, available rehabilitative therapies (pharmacological management, physiotherapy, and psychological intervention) have limited effectiveness. This study examined the effect of a 12-week intensive outpatient rehabilitation on pain relief and function in chronic CRPS patients. Rehabilitation program included memantine and morphine treatment (added to patient's prior pain medication) and concurrent psychological and physiotherapeutic intervention. Primary outcome measure was a change in CRPS symptom count and secondary outcomes were motor performance, psychological factors, pain intensity, and quality of life. Methods Ten patients with chronic upper limb CRPS I (median 2.9 years, range 8 months to 12 years) were recruited to the study and were assessed before and after the intervention. Hand motor function of the patients was evaluated by an independent physiotherapist. There were standardized questionnaires for depression, pain anxiety, pain acceptance, quality of life, and CRPS symptom count. In addition, psychological factors were evaluated by a semi-structured interview. Severity of experienced pain was rated at movement and at rest. In addition, a video experiment of a hand action observation was conducted pre- and post-intervention to study possible change in neuronal maladaptation. Intervention consisted of pharmacological, psychological and physiotherapeutic treatment. First, 10 mg daily morphine was started and increased gradually to 30 mg daily, if tolerated. After 30 mg/day or tolerated dose of morphine was achieved, 5 mg daily memantine was started and increased gradually to 40 mg, if tolerated. Psychological intervention consisted of weekly group sessions, using cognitive and behavioral methods (relaxation, behavioral activation, and exposure) and acceptance and commitment therapy (ACT) and daily home practice. Physiotherapeutic intervention consisted of graded motor imagery and physiotherapy exercises with weekly group sessions and/or individual guidance by the physiotherapist, and individual exercise of the affected upper limb. Results Multimodal intensive intervention resulted in significant decrease in CRPS symptom count. The effect was strongest in motor and trophic symptoms (19% decrease after intervention) and in sensory symptoms (18% decrease). Additionally, improvement was seen in some, but not all, secondary outcomes (movement pain, motor symptoms, change in perceptions during video experiment of hand actions, and summary index with motor functioning, pain, and psychological factors). There were no dropouts. Conclusions Intensive 12-week multimodal intervention reduced some CRPS symptoms but was not sufficient to alter patients' rest pain, distress, or quality of life. Implications These results support the efficacy of an interdisciplinary rehabilitation program for pain and function in chronic CRPS patients. After intervention, some CRPS symptoms reduced and function improved, but distress and quality of life were unchanged. This may be due to the relatively short duration of this program; to delayed effects; to particular cognitive problems of CPRS patients; and/or to low distress levels at baseline that make statistically significant reduction less likely.
Learn More >Background and aims The co-morbidity between pain and depression is a target of interest for treatment. However most of the published literature on the topic has used clinical cohorts as the population of interest. The goal of this study was to use a nationally representative sample to explore how health outcomes varied across pain and depression status in a cohort sampled from the general US population. Methods This was a cross-sectional analysis of adults ≥18 years in the 2009-2010 National Health and Nutrition Examination Survey. The cohort was stratified into: no pain/depression, pain alone, depression alone, and pain with depression. The primary outcome was self-reported general health status, and secondary outcomes were healthcare visits, overnight hospital stays and functional limitation. Survey weighted logistic regression was used to adjust for potential confounders. Results The cohort consisted of 4,213 individuals, of which 186 (4.4%) reported concurrent pain and depression. 597 (14.2%) and 253 (6.0%) were classified with either pain or depression alone, respectively. The majority of individuals with co-morbid pain and depression reported poor health (65.1%, p<0.001) and were significantly more likely than those with neither condition to rate their health as poor after adjustment (OR: 7.77, 95% CI: 4.24-14.26, p<0.001). Those with pain only or depression only were also more likely to rate their health as poor, albeit to a lesser extent (OR: 2.21, 95% CI: 1.21-2.34, p<0.001; OR: 3.75, 95% CI: 2.54-5.54, p<0.001, respectively). A similar pattern was noted across all secondary outcomes. Most notably, those with co-morbid pain and depression were the most likely to endorse functional limitation (OR: 13.15, 95% CI: 8.00-21.61, p<0.001). Comparatively, a similar trend was noted amongst those with pain only or depression only, though with a reduced effect size (OR: 4.23, 95% CI: 3.12-4.77, p<0.001; OR: 5.13, 95% CI: 3.38-7.82, p<0.001). Conclusions Co-morbid pain and depression in the general population resulted in markedly worse outcomes versus isolated pain or depression. Further, the effect appears to be synergistic. Given the substantial burdens of pain and depression, future treatments should aim to address both conditions simultaneously. Implications As a result of the co-morbidity between pain and depression, patients presenting with either condition should increase the index of suspicion among clinicians and prompt screening for the reciprocal condition. Early intervention for co-morbid pain and depression has the potential to mitigate future incidence of chronic pain and major depression.
Learn More >To determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions.
Learn More >Sickle cell disease (SCD) is characterized by hemolysis, inflammation, and pain. Mechanisms of pain manifestation are complex, and there is a major gap in knowledge of how the nervous and immune systems interact to contribute to pain and other comorbidities in SCD. Sterile inflammation in the periphery and central nervous system contributes to vascular and neural activation. Cellular and soluble mediators create an inflammatory and neuroinflammatory microenvironment contributing to neurogenic inflammation and acute and chronic pain. In this review we highlight relevant neuro-immune interactions that contribute to the pathobiology of SCD.
Learn More >Neuromodulation is nowadays investigated as a promising method for pain relief. Research indicates that a single 30-minute stimulation with transcranial pulsed electromagnetic fields (tPEMF) can induce analgesic effects. However, it is unknown whether tPEMF can induce analgesia in neuropathic pain patients.
Learn More >Repeated intravesical PAR4 (protease activated receptor 4) activation elicits persistent bladder pain lasting 5 days after the last treatment. Persistent bladder pain was fully reversed by a systemic HMGB1 (high mobility box 1) inhibitor while a MIF (macrophage migration inhibitory factor) antagonist partly reversed it. Since there is growing evidence that spinal MIF and HMGB1 mediate inflammatory and neuropathic pain we examined whether there were spinal changes occurring during persistent bladder pain that may be responsible for maintaining bladder pain. In addition, we tested whether we could modulate persistent bladder pain with spinal MIF or HMGB1 antagonists. Persistent bladder pain was elicited in female C57 mice by repeated (3x) intravesical instillation of PAR4-activating peptide while control animals received scramble peptide treatment. On day 4, spinal cord (L6-S1) changes in c-fos (non-specific marker of spinal activation) was assessed with immunofluorescence while MIF and HMGB1 were assessed with immunofluorescence, western blotting and real-time PCR. On day 7, mice received an intrathecal injection of a neutralizing MIF monoclonal antibody (15 µg in 5 µl PBS) or a HMGB1 inhibitor glycyrrhizin (25 µg in 5 µl of 5 % alcohol in PBS) and abdominal mechanical threshold was tested. On day 9, mice were treated with vehicle or control and abdominal mechanical threshold was tested. Immunofluorescence showed that c-fos and MIF in the dorsal horn, dorsal grey commissure and intermediolateral areas significantly increased in PAR4-treated mice while HMGB1 was decreased. In addition, intrathecal treatment with MIF neutralizing mAb or glycyrrhizin significantly alleviated abdominal mechanical hypersensitivity at 1 and 2 hours and the analgesic effect diminished at 6 hours. Vehicle or control treatment had no effect. Persistent bladder pain is associated with spinal changes in MIF and HMGB1 levels. Furthermore, spinal treatment with MIF monoclonal antibody and HMGB1 inhibitor temporarily reversed bladder pain. Our findings suggest that spinal MIF and HMGB1 participate in persistent bladder pain induced by repeated intravesical PAR4 and may be potential therapeutic targets in chronic bladder pain conditions.
Learn More >Disordered sleep, poor sleep quality, and insufficient or excessive sleep duration are known triggers of primary and secondary headaches. Given this, it is plausible that improving sleep will subsequently reduce headache activity. We report a systematic review of the literature, examining studies utilising psychological sleep interventions for the treatment of migraine and tension-type headache. PubMed, EMBASE, CINAHL, PsycINFO, and Cochrane Central were searched, using terms pertaining to psychological sleep interventions and headaches. Meta-analysis was performed for two outcome measures; headache frequency, and headache intensity. 103 studies were retrieved, of which 55 were duplicates. After completing reviews, three studies were retained. An additional eligible study was published after the initial search, and was found via monthly update searches, resulting in a total of four included studies. The effects of psychological sleep interventions (and in one study, combined with drug therapy) significantly reduced headache frequency and headache intensity. Three studies improved various sleep outcomes such as duration, efficiency, and excessive sleepiness. Psychological sleep interventions improve headache frequency and sleep, however there is conflicting evidence for the effect on headache intensity between studies. Limitations include the small number of studies conducted to date. Despite this, the notable improvements in headaches and sleep achieved after psychological sleep interventions indicates further research on this promising topic is warranted.
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