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Associations between obstructive sleep apnea and prescribed opioids among veterans.

Sleep disruption caused by obstructive sleep apnea (OSA) may be associated with hyperalgesia and may contribute to poor pain control and use of prescription opioids. However, the relationship between OSA and opioid prescription is not well described. We examine this association using cross-sectional data from a national cohort of veterans from recent wars enrolled from October 1, 2001 to October 7, 2014. The primary outcome was the relative risk ratio (RRR) of receiving opioid prescriptions for acute (<90 days/year) and chronic (≥90 days/year) durations compared to no opioid prescriptions. The primary exposure was a diagnosis of OSA. We used multinomial logistic regression to control for factors that may affect diagnosis of OSA or receipt of opioid prescriptions. Of the 1,149,874 patients (mean age 38.0±9.6 years) assessed, 88.1% had no opioid prescriptions, 9.4% had acute prescriptions, and 2.5% had chronic prescriptions. Ten percent had a diagnosis of OSA. Patients with OSA were more likely to be older, male, non-white, obese, current or former smokers, have higher pain intensity, and have medical and psychiatric comorbidities. Controlling for these differences, patients with OSA were more likely to receive acute (RRR 2.02 [95% CI 1.98, 2.06]) or chronic (RRR 2.15 [2.09, 2.22]) opioids. Further dividing opioid categories by high versus low dosage did not yield substantially different results. OSA is associated with a two-fold likelihood of being prescribed opioids for pain. Clinicians should consider incorporating OSA treatment into multi-modal pain management strategies; OSA as a target for pain management should be further studied.

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Increased EZH2 Levels in Anterior Cingulate Cortex Microglia Aggravate Neuropathic Pain by Inhibiting Autophagy Following Brachial Plexus Avulsion in Rats.

After brachial plexus avulsion (BPA), microglia induce inflammation, initiating and maintaining neuropathic pain. EZH2 (enhancer of zeste homolog 2) has been implicated in inflammation and neuropathic pain, but the mechanisms by which it regulates neuropathic pain remain unclear. Here, we found that EZH2 levels were markedly upregulated during BPA-induced neuropathic pain in vivo and in vitro, stimulating pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) secretion in vivo. In rats with BPA-induced neuropathic pain, mechanical and cold hypersensitivities were induced by EZH2 upregulation and inhibited by EZH2 downregulation in the anterior cingulate cortex. Microglial autophagy was also significantly inhibited, with EZH2 inhibition activating autophagy and reducing neuroinflammation in vivo. However, this effect was impaired by inhibiting autophagy with 3-methyladenine, suggesting that the MTOR signaling pathway is a functional target of EZH2. These data suggest that EZH2 regulates neuroinflammation and neuropathic pain via a novel MTOR-mediated autophagy signaling pathway, providing a promising approach for managing neuropathic pain.

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Motor cortex stimulation in chronic neuropathic orofacial pain syndromes: a systematic review and meta-analysis.

Invasive motor Cortex Stimulation (iMCS) was introduced in the 1990's for the treatment of chronic neuropathic orofacial pain (CNOP), although its effectiveness remains doubtful. However, CNOP is known to be a heterogeneous group of orofacial pain disorders, which can lead to different responses to iMCS. Therefore, this paper investigated (1) whether the effectiveness of iMCS is significantly different among different CNOP disorders and (2) whether other confounding factors can be impacting iMCS results in CNOP. A systematic review and meta-analysis using a linear mixed-model was performed. Twenty-three papers were included, totaling 140 CNOP patients. Heterogeneity of the studies showed to be 55.8%. A visual analogue scale (VAS) measured median pain relief of 66.5% (ranging from 0-100%) was found. Linear mixed-model analysis showed that patients suffering from trigeminal neuralgia responded significantly more favorable to iMCS than patients suffering from dysfunctional pain syndromes (p = 0.030). Also, patients suffering from CNOP caused by (supra)nuclear lesions responded marginally significantly better to iMCS than patients suffering from CNOP due to trigeminal nerve lesions (p = 0.049). No other confounding factors were elucidated. This meta-analysis showed that patients suffering from trigeminal neuralgia and patients suffering from (supra)nuclear lesions causing CNOP responded significantly more favorable than others on iMCS. No other confounding factors were found relevant.

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Vancouver Declaration II on Global Headache Patient Advocacy 2019.

In 2017, the International Headache Society convened a Global Patient Advocacy Summit (GPAS-1) to begin a collaborative effort involving patients, patient advocates, patient advocacy organizations, healthcare professionals, scientists, professional pain, neurology, and headache societies, pharmaceutical manufacturers, and regulatory agencies to advance issues of importance to patients affected by headache worldwide. In September 2019, the second Global Patient Advocacy Summit (GPAS-2) was convened to revisit issues from the inaugural meeting, assess the progress of the International Headache Society Global Patient Advocacy Coalition (IHS-GPAC) in meeting the goals set forth therein, and discuss strategies for achieving established goals and supporting future development. Short- and long-term mandates from the first Summit were realized, including publishing the Vancouver Declaration on Global Headache Patient Advocacy 2018, determining the governing and operational structures of the IHS-GPAC, and helping to facilitate the first World Federation of Neurology World Brain Day dedicated to migraine. Another short-term mandate, creating a unified advocacy strategy, was fulfilled by the Coalition's decision to focus on encouraging support from employers and implementing employee support programs for people with migraine. To help execute the strategy, the Coalition is developing an employer engagement toolkit that will educate employers and employees about the impact of migraine in the workplace, reduce stigma directed toward employees with migraine, and facilitate the care of employees with migraine to reduce the burden of illness and improve workplace productivity. Coalition members will disseminate the toolkit and encourage the adoption of migraine workplace programs by employers worldwide. The Coalition has established an alliance with two global, multinational employers to expand migraine awareness and support among policy makers and other stakeholders around the world. The IHS-GPAC met many of the goals established at GPAS-1, and it has initiated a global strategy focused on the psychosocial and economic toll of headache disorders, especially migraine, in the workplace. Ongoing and future activities will explore a range of opportunities with employers and across the full spectrum of advocacy goals.

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Local Ca signals couple activation of TRPV1 and ANO1 sensory ion channels.

ANO1 (TMEM16A) is a Ca-activated Cl channel (CaCC) expressed in peripheral somatosensory neurons that are activated by painful (noxious) stimuli. These neurons also express the Ca-permeable channel and noxious heat sensor TRPV1, which can activate ANO1. Here, we revealed an intricate mechanism of TRPV1-ANO1 channel coupling in rat dorsal root ganglion (DRG) neurons. Simultaneous optical monitoring of CaCC activity and Ca dynamics revealed that the TRPV1 ligand capsaicin activated CaCCs. However, depletion of endoplasmic reticulum (ER) Ca stores reduced capsaicin-induced Ca increases and CaCC activation, suggesting that ER Ca release contributed to TRPV1-induced CaCC activation. ER store depletion by plasma membrane-localized TRPV1 channels was demonstrated with an ER-localized Ca sensor in neurons exposed to a cell-impermeable TRPV1 ligand. Proximity ligation assays established that ANO1, TRPV1, and the IP receptor IPR1 were often found in close proximity to each other. Stochastic optical reconstruction microscopy (STORM) confirmed the close association between all three channels in DRG neurons. Together, our data reveal the existence of ANO1-containing multichannel nanodomains in DRG neurons and suggest that coupling between TRPV1 and ANO1 requires ER Ca release, which may be necessary to enhance ANO1 activation.

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No association between migraine frequency and white matter lesions and silent brain infarctions: a study in a series of chronic migraine women.

It has been suggested that silent infarctions (SI) and hyperintense white matter lesions (WML) are related to migraine frequency. We studied their prevalence and anatomical distribution in chronic migraine (CM) patients.

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Pressure pain sensitivity in patients with traumatic first-time and recurrent anterior shoulder dislocation: a cross-sectional analysis.

Background and aims Traumatic anterior shoulder dislocation (ASD) is frequent in active populations and associated with a 39% higher risk of recurrent dislocation, which may cause persistent shoulder problems, pain, and impaired shoulder-related quality of life. While local and distant pressure pain sensitivity has been demonstrated in other shoulder conditions, little is known about the link between pressure pain sensitivity and ASD. The interesting aspect is whether recurrent dislocation – resulting in symptoms of longer duration – is associated with more pronounced pressure pain sensitivity, or if presence of pressure pain sensitivity may be part of the reasons why patients develop recurrent dislocation. Therefore, this study aimed at evaluating whether patients with recurrent ASD display greater pressure pain sensitivity and more painful body sites than patients with first-time ASD. Methods This was a cross-sectional analysis of baseline data from a randomized controlled trial including 34 patients with first-time ASD [82% male, mean (SD) age 26 (7) years] and 22 patients with recurrent ASD [96% male, mean (SD) age 25 (5) years]. Patients were assessed as follows: (1) assessment of local and distant pressure pain sensitivity evaluated by pressure pain thresholds (PPTs) using a handheld algometer on mm. trapezius superior, levator scapula, pectorales major, deltoideus, and tibialis anterior, (2) pain intensity at rest during the previous 24 h, (3) number of ASD, and (4) number of painful body sites on a region-divided body chart. Results The PPTs were not significantly different between first-time and recurrent ASD [mean (SD) kPa for m. trapezius superior 264 (110) vs. 261 (88), m. levator scapula 301 (157) vs. 325 (163), m. pectorales major 234 (163) vs. 269 (130), m. deltoideus 290 (166) vs. 352 (173), m. tibialis anterior 420 (202) vs. 449 (184)], two-way ANCOVA, adjusted for sex and age, F (4,263) = 0.29, p = 0.88. For both groups, the PPTs were lower at the shoulder sites than at m. tibialis anterior (difference 117-184 kPa, 95% CI range 33-267). Females had lower PPTs than males (difference 124 kPa, 95% CI 64-183). The number (SD) of painful body sites were 2.2 (1.9) for first-time ASD and 2.6 (5.4) for recurrent ASD, with no between-group differences, one-way ANCOVA, adjusted for sex and age, F (1, 52) = 0.24, p = 0.63. There was a strong correlation between PPTs at the shoulder and lower leg, r = 0.84, p < 0.01. Conclusions This study demonstrated no differences in local and distant pressure pain sensitivity or number of painful body sites between patients with first-time and recurrent ASD. Females had lower PPTs than males, and a strong correlation was found between PPTs at the shoulder and lower leg. Implications Patients with first-time and recurrent ASD seem to have similar pressure pain sensitivity, but lower PPTs compared to existing normative data, suggesting that it is relevant to evaluate the status of the pain system in these patients to prevent triggering or worsening of their symptoms. However, it remains unanswered how these changes affect the patients' ability to undergo rehabilitation, symptom response and long-term shoulder function.

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Local hyperalgesia, normal endogenous modulation with pain report beyond its origin: a pilot study prompting further exploration into plantar fasciopathy.

Background and aims Persistent tendinopathies were previously considered solely as peripheral conditions affecting the local tendinous tissue until quantitative sensory testing identified involvement of altered pain processing. In similar fashion, pain in patients with persistent plantar fasciopathy may also involve more than local tissue. The aim of this pilot study was to investigate potential differences in conditioned pain modulation and pressure and thermal pain thresholds, between individuals with PF and healthy pain-free controls, as a precursor to a larger-scale study. Methods We assessed 16 individuals with plantar fasciopathy and 11 pain-free controls. Plantar fasciopathy diagnosis was: palpation pain of the medial calcaneal tubercle or the proximal plantar fascia, duration ≥3 months, pain intensity ≥2/10, and ultrasound-measured plantar fascia thickness ≥4 mm. Quantitative sensory tests were performed locally at the plantar heel and remotely on the ipsilateral elbow. Assessments included pain thresholds for pressure, heat and cold, and conditioned pain modulation measured as change in local resting pressure pain threshold with cold water hand immersion. Participants rated pain intensity at pain threshold. Additionally, the area and distribution of plantar fasciopathy pain was drawn on a digital body chart of the lower limbs. Descriptive analyses were performed and between-group differences/effects expressed as standardised mean differences (d). Results There was no conditioned pain modulation difference between participants with plantar fasciopathy and controls (d = 0.1). Largest effects were on local pressure pain threshold and reported pain intensity on pressure pain threshold (d > 1.8) followed by pain intensity for heat and cold pain thresholds (d = 0.3-1.5). According to the digital body chart, pain area extended beyond the plantar heel. Conclusions The unlikelihood of a difference in conditioned pain modulation yet a pain area extending beyond the plantar heel provide a basis for exploring altered pain processing in a larger-scale study. Implications This was the first study to investigate the presence of altered pain processing in individuals with plantar fasciopathy using a conditioned pain modulation paradigm and thermal pain thresholds. We found no indication of an altered pain processing based on these measures, however, patients rated pain higher on thresholds compared to controls which may be important to clinical practice and warrants further exploration in the future.

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An observational study on risk factors for prolonged opioid prescription after severe trauma.

Trauma is one of the most common causes of morbidity and mortality in people of working age. Following surgery, approximately 10% of patients develop persistent postsurgical pain. Chronic pain is a complex phenomenon that can adversely affect quality of life and is associated with psychiatric conditions such as anxiety and depression. Pharmacological treatment is normally insufficient to fully alleviate chronic pain and improve functional capacity, especially in the long term. The appropriateness of opioid treatment in chronic non-cancer pain has become increasingly examined with high numbers of serious side effects including drug dependency and death. The present study was based on clinical observations suggesting that a problematic opioid use can be initiated during trauma care, which implies the importance of evaluating opioid therapy and its effect on trauma patients. Specific attention is given to patients with known psychiatric conditions which may render them more vulnerable to develop problematic opioid use. The aim of this observational study was to broadly characterize patients referred to a pain specialist after severe trauma regarding their trauma type, psychiatric co-morbidity, and opioid prescription pattern. This was done to tentatively investigate possible risk factors for long-term opioid use following trauma.

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The development of a novel questionnaire assessing alterations in central pain processing in people with and without chronic pain.

Background and aims The purpose of this study was to (a) develop and (b) conduct exploratory factor analysis on a novel self-report instrument for symptoms associated with altered central pain processing. Methods We first developed a 25-item questionnaire based on previous literature identifying symptoms and behaviours that may reflect altered spinal and supraspinal pain processing. We then administered this questionnaire to 183 people with chronic pain (n = 99) and healthy individuals (n = 84). Exploratory factor analysis was conducted to identify the factor structure of the questionnaire. Results Our results support a two-factor solution for the 25-item questionnaire that accounted for 57.2% of the total variance of responses in people with and without chronic pain. Factor one (11 items) included items related to alterations in sensation of pain, while factor two (seven items) included items associated with emotional and fatigue symptoms. Seven items showed weak factor loadings and were eliminated. Reliability was excellent, while both factors showed strong correlations with previously-validated self-report Instruments: (pain catastrophising, mood, vigilance, pain self-efficacy) and conditioned pain modulation, providing evidence for their validity. Conclusions We have developed a questionnaire containing two factors that appear to be related to two different symptom clusters, one of which is specifically related to pain and one of which contains other health-related symptoms related to mood and fatigue. These factors show excellent internal consistency and validity. This questionnaire may be a quick, easy and reliable instrument to assess central pain processing in clinical settings.

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