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Chronic pain is a significant global health issue. For most individuals with chronic pain, biomedical treatments do not provide adequate relief. Given the evidence that neurophysiological abnormalities are associated with pain, it is reasonable to consider treatments that target these factors, such as neurofeedback (NF). The primary objectives of this review were to summarize the current state of knowledge regarding: (1) the different types of NF and NF protocols that have been evaluated for pain management; (2) the evidence supporting each NF type and protocol; (3) if targeted brain activity changes occur with NF training; and (4) if such brain activity change is associated with improvements on treatment outcomes. Inclusion criteria were intentionally broad to encompass every empirical study using NF in relation to pain. We considered all kinds of NF, including both electroencephalogram- (EEG-) and functional magnetic resonance imagining- (fMRI-) based. We searched the following databases from inception through September 2019: Pubmed, Ovid, Embase, Web of Science, PsycINFO. The search strategy consisted of a combination of key terms referring to all NF types and pain conditions (e.g., neurofeedback, rt-fMRI-NF, BOLD, pain, migraine). A total of 6,552 citations were retrieved; 24 of these that were included in the review. Most of the studies were of moderate quality, included a control condition and but did not include a follow-up. They focused on studying pain intensity (83%), pain frequency, and other variables (fatigue, sleep, depression) in samples of adults ( = 7-71) with headaches, fibromyalgia and other pain conditions. Most studies (79%) used EEG-based NF. A wide variety of NF types and protocols have been used for pain management aiming to either increase, decrease or regulate brain activity in certain areas theoretically associated with pain. Given the generally positive results in the studies reviewed, the findings indicate that NF procedures have the potential for reducing pain and improving other related outcomes in individuals with chronic pain. However, the current evidence does not provide definitive conclusions or allow for reliable recommendations on which protocols or methods of administration may be the most effective. These findings support the need for continued – but higher quality – research in this area.
Learn More >Acid-sensing ion channels (ASICs) are of the most sensitive molecular sensors of extracellular pH change in mammals. Six isoforms of these channels are widely represented in membranes of neuronal and non-neuronal cells, where these molecules are involved in different important regulatory functions, such as synaptic plasticity, learning, memory, and nociception, as well as in various pathological states. Structural and functional studies of both wild-type and mutant ASICs are essential for human care and medicine for the efficient treatment of socially significant diseases and ensure a comfortable standard of life. Ligands of ASICs serve as indispensable tools for these studies. Such bioactive compounds can be synthesized artificially. However, to date, the search for such molecules has been most effective amongst natural sources, such as animal venoms or plants and microbial extracts. In this review, we provide a detailed and comprehensive structural and functional description of natural compounds acting on ASICs, as well as the latest information on structural aspects of their interaction with the channels. Many of the examples provided in the review demonstrate the undoubted fundamental and practical successes of using natural toxins. Without toxins, it would not be possible to obtain data on the mechanisms of ASICs' functioning, provide detailed study of their pharmacological properties, or assess the contribution of the channels to development of different pathologies. The selectivity to different isoforms and variety in the channel modulation mode allow for the appraisal of prospective candidates for the development of new drugs.
Learn More >The Strategy for Patient-Oriented Research Chronic Pain Network was founded in 2016 and is a patient-oriented research network funded by the Canadian Institutes of Health Research. The Network incorporates patient partners throughout its governance and operations meaning that patient partners may contribute to research projects in ways that warrant scientific authorship as defined by the International Committee of Medical Journal Editors. The Network did a brief informal review of guidance on patient authorship in 2019, but could not find any practical documentation to guide its members on this topic. Note the term patient partner here refers to a patient (or caregiver or other person with lived experience) who is a partner or collaborator on a research team. This guidance does not address patients as participants in a research study. This guidance has been co-written by a group of researchers and patient partners of the Chronic Pain Network in an effort to address this gap. It is intended for both researchers and patient partner audiences. This guidance is meant to facilitate conversations between researchers and patient partners about authorship and/or acknowledgement regarding research projects on which they collaborate. While the overall principles of academic authorship and acknowledgement remain unchanged, nuances for interpreting these principles through the lens of patient engagement or patient-oriented research is provided. Teams that carry out patient-oriented research projects will require different preparation to empower all team members (researchers and patient partners) to discuss authorship and acknowledgement. To facilitate these conversations, we have included an overview of the scientific publishing process, explanation of some common terms, and sets of considerations are provided for both patient partners and researchers in determining the range of team member contribution from acknowledgement to authorship. Conversations about authorship can be difficult, even for established research teams. This guidance, and the resources discussed within it, are provided with the intention of making these conversations easier and more thoughtful.
Learn More >Chronic pain prevalence is high worldwide and increases at older ages. Signs of premature aging have been associated with chronic pain, but few studies have investigated aging biomarkers in pain-related conditions. A set of DNA methylation (DNAm)-based estimates of age, called "epigenetic clocks," has been proposed as biological measures of age-related adverse processes, morbidity, and mortality. The aim of this study is to assess if different pain-related phenotypes show alterations in DNAm age. In our analysis, we considered three cohorts for which whole-blood DNAm data were available: heat pain sensitivity (HPS), including 20 monozygotic twin pairs discordant for heat pain temperature threshold; fibromyalgia (FM), including 24 cases and 20 controls; and headache, including 22 chronic migraine and medication overuse headache patients (MOH), 18 episodic migraineurs (EM), and 13 healthy subjects. We used the Horvath's epigenetic age calculator to obtain DNAm-based estimates of epigenetic age, telomere length, levels of 7 proteins in plasma, number of smoked packs of cigarettes per year, and blood cell counts. We did not find differences in epigenetic age acceleration, calculated using five different epigenetic clocks, between subjects discordant for pain-related phenotypes. Twins with high HPS had increased CD8+ T cell counts (nominal = 0.028). HPS thresholds were negatively associated with estimated levels of GDF15 (nominal = 0.008). FM patients showed decreased naive CD4+ T cell counts compared with controls (nominal = 0.015). The severity of FM manifestations expressed through various evaluation tests was associated with decreased levels of leptin, shorter length of telomeres, and reduced CD8+ T and natural killer cell counts (nominal < 0.05), while the duration of painful symptoms was positively associated with telomere length (nominal = 0.034). No differences in DNAm-based estimates were detected for MOH or EM compared with controls. In summary, our study suggests that HPS, FM, and MOH/EM do not show signs of epigenetic age acceleration in whole blood, while HPS and FM are associated with DNAm-based estimates of immunological parameters, plasma proteins, and telomere length. Future studies should extend these observations in larger cohorts.
Learn More >Reduced pain tolerance may be one of the possible explanations for high prevalence of chronic pain among older people. We hypothesized that age-related alterations in pain tolerance are associated with functioning deterioration of the frontal cortex during normal aging. Twenty-one young and 41 elderly healthy participants underwent a tonic heat pain test, during which cerebral activity was recorded using electroencephalography (EEG). Elderly participants were divided into two subgroups according to their scores on executive tests, high performers (HPs; = 21) and low performers (LPs; = 20). Pain measures [exposure times (ETs) and perceived pain ratings] and cerebral activity were compared among the three groups. ETs were significantly lower in elderly LPs than in young participants and elderly HPs. Electroencephalographic analyses showed that gamma-band oscillations (GBOs) were significantly increased in pain state for all subjects, especially in the frontal sites. Source analysis showed that GBO increase in elderly LPs was contributed not only by frontal but also by central, parietal, and occipital regions. These findings suggest that better preservation of frontal functions may result in better pain tolerance by elderly subjects.
Learn More >Veterans frequently seek chronic pain care from their primary care providers (PCPs) who may not be adequately trained to provide pain management. To address this issue the Veterans Health Administration (VHA) Office of Specialty Care adopted the Specialty Care Access Network Extension for Community Healthcare Outcomes (VA-ECHO née SCAN-ECHO). The VA-ECHO program offered training and mentoring by specialists to PCPs and their staff. VA-ECHO included virtual sessions where expertise was shared in two formats: (1) didactics on common pain conditions, relevant psychological disorders, and treatment options and (2) real-time consultation on patient cases. VA-ECHO participants' perspectives were obtained using a semi-structured interview guide designed to elicit responses based on the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework. A convenience sampling was used to recruit PCPs and non-physician support staff participants. Non-physicians from rural VHA sites were purposively sampled to gain diverse perspectives. This qualitative study yielded data on each RE-AIM domain except reach. Program reach was not measured as it is outside the scope of this study. Respondents reported program effectiveness as gains in knowledge and skills to improve pain care delivery. Effective incorporation of learning into practice was reflected in respondents' perceptions of improvements in: patient engagement, evidenced-based approaches, appropriate referrals, and opioid use. Program adoption included how participating health care systems selected trainees from a range of sites and roles to achieve a wide reach of pain expertise. Participation was limited by time to attend and facilitated by institutional support. Differences and similarities were noted in implementation between hub sites. Maintenance was revealed when respondents noted the importance of the lasting relationships formed between fellow participants. This study highlights VA-ECHO program attributes and unintended consequences. These findings are expected to inform future use of VA-ECHO as a means to establish a supportive consultation network between primary and specialty care providers to promote the delivery evidence-based pain management practices.
Learn More >Topical analgesics are an upcoming treatment option for neuropathic pain. In this observational study, we performed a double-blind placebo-controlled response test (DOBRET) in patients with polyneuropathy to determine the personalized analgesic effect of phenytoin 10% cream.
Learn More >Pain in sickle cell disease (SCD) is severe and multifaceted resulting in significant differences in its frequency and intensity among individuals. In this study, we examined the influence of S100B gene single nucleotide polymorphisms (SNP) on acute and chronic pain variability in SCD.
Learn More >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.
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