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In the United States (US), long-term opioid therapy has been commonly prescribed for chronic pain. Since recognition of the opioid overdose epidemic, clinical practice guidelines have recommended tapering long-term opioids to reduced doses or discontinuation. The Effects of Prescription Opioid Changes for veterans (EPOCH) study is a national population-based prospective observational study of US Veterans Health Administration primary care patients designed to assess effects of evolving opioid prescribing practice on patients treated with long-term opioids for chronic pain. A stratified random sampling design was used to identify a survey sample from the target population of patients treated with opioid analgesics for ≥ 6 months. Demographic, diagnostic, visit, and pharmacy dispensing data were extracted from existing datasets. A 2016 mixed-mode mail and telephone survey collected patient-reported data, including the main patient-reported outcomes of pain-related function (Brief Pain Inventory interference; BPI-I scores 0-10, higher scores = worse) and health-related quality of life. Data on survey participants and non-participants were analyzed to assess potential nonresponse bias. Weights were used to account for design. Linear regression models were used to assess cross-sectional associations of opioid treatment with patient-reported measures. Of 14,160 patients contacted, 9253 (65.4%) completed the survey. Participants were older than non-participants (63.9 ± 10.6 vs. 59.6 ± 13.0 years). The mean number of bothersome pain locations was 6.8 (SE 0.04). Effectiveness of pain treatment and quality of pain care were rated fair or poor by 56.1% and 45.3%, respectively. The opioid daily dosage range was 1.6 to 1038.2 mg, with mean = 50.6 mg (SE 1.1) and median = 30.9 mg (IQR 40.7). Among the 73.2% of patients who did not receive long-acting opioids, the mean daily dosage was 30.4 mg (SE 0.6) and mean BPI-I was 6.4 (SE 00.4). Among patients who received long-acting opioids, the mean daily dosage was 106.2 mg (SE 2.8) and mean BPI-I was 6.8 (SE 0.07). Higher daily dosage was associated with worse pain-related function and quality of life among patients without long-acting opioids, but not among patients with long-acting opioids. Future analyses will use follow-up data to examine effects of opioid dose reduction and discontinuation on patient outcomes.
Learn More >Neuroimaging studies have demonstrated that altered activity in somatosensory and motor cortices play a key role in pain chronification. Neurofeedback training of sensorimotor rhythm (SMR) is a tool which allow individuals to self-modulate their brain activity and to produce significant changes over somatomotor brain areas. Several studies have further shown that neurofeedback training may reduce pain and other pain-related symptoms in chronic pain patients. The goal of the present study was to analyze changes in SMR power and brain functional connectivity of the somatosensory and motor cortices elicited by neurofeedback task designed to both synchronize and desynchronize the SMR power over motor and somatosensory areas in fibromyalgia patients. Seventeen patients were randomly assigned to the SMR training ( = 9) or to a sham protocol ( = 8). All participants were trained during 6 sessions, and fMRI and EEG power elicited by synchronization and desynchronization trials were analyzed. In the SMR training group, four patients achieved the objective of SMR modulation in more than 70% of the trials from the second training session (good responders), while five patients performed the task at the chance level (bad responders). Good responders to the neurofeedback training significantly reduced pain and increased both SMR power modulation and functional connectivity of motor and somatosensory related areas during the last neurofeedback training session, whereas no changes in brain activity or pain were observed in bad responders or participants in the sham group. In addition, we observed that good responders were characterized by reduced impact of fibromyalgia and pain symptoms, as well as by increased levels of health-related quality of life during the pre-training sessions. In summary, the present study revealed that neurofeedback training of SMR elicited significant brain changes in somatomotor areas leading to a significant reduction of pain in fibromyalgia patients. In this sense, our research provide evidence that neurofeedback training is a promising tool for a better understanding of brain mechanisms involved in pain chronification.
Learn More >Opioid receptors comprise μ (MOP), δ (DOP), κ (KOP), and nociceptin/orphanin FQ (NOP) receptors. Opioids are agonists of MOP, DOP, and KOP receptors, whereas nociceptin/orphanin FQ (N/OFQ) is an agonist of NOP receptors. Activation of all four opioid receptors in neurons can induce analgesia in animal models, but the most clinically relevant are MOP receptor agonists (e.g., morphine, fentanyl). Opioids can also affect the function of immune cells, and their actions in relation to immunosuppression and infections have been widely discussed. Here, we analyze the expression and the role of opioid receptors in peripheral immune cells and glia in the modulation of pain. All four opioid receptors have been identified at the mRNA and protein levels in immune cells (lymphocytes, granulocytes, monocytes, macrophages) in humans, rhesus monkeys, rats or mice. Activation of leukocyte MOP, DOP, and KOP receptors was recently reported to attenuate pain after nerve injury in mice. This involved intracellular Ca-regulated release of opioid peptides from immune cells, which subsequently activated MOP, DOP, and KOP receptors on peripheral neurons. There is no evidence of pain modulation by leukocyte NOP receptors. More good quality studies are needed to verify the presence of DOP, KOP, and NOP receptors in native glia. Although still questioned, MOP receptors might be expressed in brain or spinal cord microglia and astrocytes in humans, mice, and rats. Morphine acting at spinal cord microglia is often reported to induce hyperalgesia in rodents. However, most studies used animals without pathological pain and/or unconventional paradigms (e.g., high or ultra-low doses, pain assessment after abrupt discontinuation of chronic morphine treatment). Therefore, the opioid-induced hyperalgesia can be viewed in the context of dependence/withdrawal rather than pain management, in line with clinical reports. There is convincing evidence of analgesic effects mediated by immune cell-derived opioid peptides in animal models and in humans. Together, MOP, DOP, and KOP receptors, and opioid peptides in immune cells can ameliorate pathological pain. The relevance of NOP receptors and N/OFQ in leukocytes, and of all opioid receptors, opioid peptides and N/OFQ in native glia for pain control is yet to be clarified.
Learn More >Recently, clinicians have been using repetitive transcranial magnetic stimulation (rTMS) for treating various pain conditions. This systematic narrative review aimed to examine the use and efficacy of rTMS for controlling various pain conditions. A PubMed search was conducted for articles that were published until June 7, 2019 and used rTMS for pain alleviation. The key search phrase for identifying potentially relevant articles was (repetitive transcranial magnetic stimulation AND pain). The following inclusion criteria were applied for article selection: (1) patients with pain, (2) rTMS was applied for pain management, and (3) follow-up evaluations were performed after rTMS stimulation to assess the reduction in pain. Review articles were excluded. Overall, 1,030 potentially relevant articles were identified. After reading the titles and abstracts and assessing eligibility based on the full-text articles, 106 publications were finally included in our analysis. Overall, our findings suggested that rTMS is beneficial for treating neuropathic pain of various origins, such as central pain, pain from peripheral nerve disorders, fibromyalgia, and migraine. Although data on the use of rTMS for orofacial pain, including trigeminal neuralgia, phantom pain, low back pain, myofascial pain syndrome, pelvic pain, and complex regional pain syndrome, were promising, there was insufficient evidence to determine the efficacy of rTMS for treating these conditions. Therefore, further studies are needed to validate the effects of rTMS on pain relief in these conditions. Overall, this review will help guide clinicians in making informed decisions regarding whether rTMS is an appropriate option for managing various pain conditions.
Learn More >We conducted a feasibility 2×2 factorial trial comparing N-methyl-D-aspartate (NMDA) antagonists (intravenous ketamine and oral memantine) versus placebo and intravenous steroids versus placebo, in patients having elective video-assisted thoracic surgery lobectomies, at St. Joseph's Hamilton, Canada, and Cleveland Clinic, Cleveland, USA. Our feasibility objectives were: 1) recruitment rate/week; 2) recruitment of ≥90% of eligible patients; and 3) >90% follow-up. Secondary objectives were incidence and intensity of persistent post-surgical pain (PPSP) and other clinical and safety outcomes.
Learn More >Neurophysiological mechanisms leading to chronicity of pruritus are not yet fully understood and it is not known whether these mechanisms diverge between different underlying diseases of chronic pruritus. This study aimed to detect such mechanisms in chronic pruritus of various origins. One-hundred and twenty patients with chronic pruritus of inflammatory origin (atopic dermatitis), neuropathic origin (brachioradial pruritus) and chronic prurigo of nodular type, the latter as a model for chronic scratching, as well as 40 matched healthy controls participated in this study. Stimulation with cowhage induced a more intensive itch sensation compared to stimulation with other substances in all patient groups but not in healthy controls, arguing for sensitisation of cutaneous mechano- and heat-sensitive C-fibers in chronic pruritus. All patient groups showed a decreased intraepidermal nerve fibre density compared to controls. A decreased condition pain modulation effect was observed in all patient groups compared to controls, suggesting a reduced descending inhibitory system in chronic pruritus. In sum, chronic pruritus of different etiology showed a mixed peripheral and central pattern of neuronal alterations, which might contribute to the chronicity of pruritus with no differences between pruritus entities. Our findings may contribute to the development of future treatment strategies targeting these pathomechanisms.
Learn More >Sickle cell disease is a uniquely complex painful disease, with lifelong episodes of unpredictable acute pain and superimposed chronic pain in adulthood. Both painful crises and chronic pain in sickle cell disease lack strong objective pathological correlates and their mechanisms are poorly understood. Opioids have emerged as the standard of care for severe acute pain in sickle cell disease and many patients with chronic pain are maintained on chronic opioid therapy. The strong association between recurrent acute pain and chronic pain in SCD blurs the distinction between acute and chronic opioid management paradigms. In addition, opioid management for SCD is dogged by stigma and concerns regarding addiction. This review aims to synthesize the broad literature on opioids to highlight the clinical complexity of opioid management in sickle cell disease and suggest directions for future research and clinical innovation.
Learn More >To examine the characteristics of primary stabbing headache (PSH) in typically developing children and adolescents.
Learn More >Psychological interventions designed to enhance positive affect are promising ways to promote adaptive functioning in people with chronic pain. However, few studies have addressed the efficacy of positive affect interventions in chronic pain populations and examined which patients can benefit more from them. The aim of the present study was to identify mediators and moderators of the best possible self intervention (BPS) in fibromyalgia patients.
Learn More >Emerging evidence has indicated that colony-stimulating factor-1 (CSF1) modulates neuroinflammation in the central nervous system (CNS) and the development of neuropathic pain, while the underlying mechanism remains unknown. Here, we identified the increased expression of CSF1 derived from activated astrocytes in the ipsilateral dorsal horn in rats with spinal nerve ligation (SNL). Suppression of CSF1 expression alleviated neuroinflammation, neuronal hyperexcitability and glutamatergic receptor subunit upregulation in the dorsal horn and improved SNL-induced pain behavior. We also found reduced miR-214-3p expression in the ipsilateral dorsal horn following an SNL procedure; miR-214-3p directly bound to the 3'-UTR of CSF1 mRNA and negatively regulated CSF1 expression. Intrathecal delivery of miR-214-3p mimic reversed the enhanced expression of CSF1 and astrocyte overactivity and alleviated the IL-6 upregulation and pain behavior induced by SNL. Moreover, suppression of spinal miR-214-3p increased astrocyte reactivity, promoted CSF1 and IL-6 production, and induced pain hypersensitivity in naïve animals. Furthermore, SNL induced the expression of DNA methyltransferase 3a (DNMT3a) that was associated with the hypermethylation of the miR-214-3p promoter, leading to reduced miR-214-3p expression in the model rodents. Treatment with the DNMT inhibitor zebularine significantly reduced cytosine methylation in the miR-214-3p promoter; this reduced methylation consequently increased the expression of miR-214-3p and decreased the content of CSF1 in the ipsilateral dorsal horn, and further, attenuated IL-6 production and pain behavior in rats with SNL. Together, our data indicate that the DNMT3a-mediated epigenetic suppression of miR-214-3p enhanced CSF1 production in astrocytes, which subsequently induced neuroinflammation and pain behavior in SNL model rats.
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