Browse by Audience
Neuropathic pain (NeuP) can be difficult to diagnose and manage in children. Data regarding prevalence and sex-dependent differences are limited, and more detailed phenotyping is needed. This observational cohort study recruited adolescents (10-17 years) with NeuP or complex regional pain syndrome (CRPS). After pain history and NeuP questionnaires, quantitative sensory testing was performed. Individual z-score plots were calculated with body-region control measures and matched to mechanism-related sensory profiles (sensory loss, thermal hyperalgesia, and mechanical hyperalgesia). Conditioned pain modulation was assessed with pressure pain threshold and a contralateral cold conditioning stimulus, and meaningful conditioned pain modulation defined as twice the standard error of measurement. Patients and parents completed validated questionnaires for child quality of life (QoL), pain catastrophizing, and self-reported anxiety/depression. Males (n = 23) and females (n = 43) with NeuP (n = 52) or CRPS (n = 14) reported moderate-severe pain with neuropathic sensory descriptors. Mixed patterns of sensory gain/loss at pain sites were not sex-dependent. Thermal hyperalgesia was common in both NeuP and CRPS, whereas sensory loss occurred only with NeuP and in a smaller proportion than adult cohorts. Conditioned pain modulation was inhibitory in 54%, facilitatory in 14%, and nonresponders had variable cold conditioning sensitivity. Males and females reported marked impairment of QoL, increased emotional distress, and pain catastrophising. Child-parent QoL scores correlated, but catastrophizing scores were discordant when parents or adolescents reported higher anxiety/depression. NeuP in adolescents is associated with significant pain, physical impairment, and psychosocial impairment. Quantifying alterations in somatosensory profiles, descending modulation, child and parent psychological function will inform individualized therapy and stratification for future clinical trials.
Learn More >Chronic pain is associated with mental and physical health difficulties and is prevalent among veterans. Cannabis has been put forth as a treatment for chronic pain, and changes in laws, attitudes, and use patterns have occurred over the last two decades. Differences in prevalence of non-medical cannabis use and cannabis use disorder (CUD) were examined across two groups: veterans/non-veterans and those reporting/not reporting recent pain. Data from the National Epidemiologic Survey on Alcohol and Related Conditions-III (2012-2013; n=36,309) were analyzed using logistic regression. Prevalence Differences (PD) for three cannabis outcomes: (1) past-year non-medical cannabis use, (2) frequent (≥3 times a week) non-medical use, and (3) DSM-5 CUD were estimated for those reporting recent moderate-severe pain (veterans/non-veterans), and veterans reporting/not reporting recent pain. Difference in differences were calculated to investigate prevalence differences on outcomes associated with residence in a state with medical cannabis laws (MCLs). Associations between physical and mental health and cannabis variables were tested. Results indicated that the prevalence of recent pain was greater among veterans (PD=7.25%, 95% CI [4.90, 9.60]). Among veterans, the prevalence of frequent cannabis use was greater among those with pain (PD=1.92%, 98% CI [0.21, 3.63]), and, among veterans residing in a state with MCLs, the prevalence of CUD was greater among those reporting recent pain (PD=3.88%, 98% CI [0.36, 7.39]). Findings failed to support the hypothesis that cannabis use improves mental or physical health for veterans with pain. Providers treating veterans with pain in MCL states should monitor such patients closely for CUD.
Learn More >Migraine is one of the most common neurological disorders characterized by recurrent attacks of typically throbbing and unilateral headaches, affecting up to 20 % of the population worldwide. Despite the high prevalence and severity of this primary headache disorder, it remains to be a challenge to fully understand and treat migraine headaches. By characterizing and validating a mouse migraine model, this study aimed to investigate the functional contribution of PKC isoforms in migraine. In this study, we identified the presence of migraine-like ongoing pain in mice after chronic intermittent treatment with nitroglycerin (NTG). The peptide antagonist of calcitonin gene related peptide (CGRP) α-CGRP (8-37), but not topiramate nor sumatriptan, effectively blocked ongoing pain and elicited pain relief-induced CPP in NTG-treated mice. Prominent activation of PKCδ was observed in chronic NTG-treated mice. Functional inhibition of PKCδ significantly attenuated ongoing spontaneous pain in chronic NTG-treated mice. Furthermore, we recapitulated the NTG-triggered migraine behavior in wild-type, but not in PKCδ-null mice. In response to repeated administration of NTG, ongoing spontaneous pain was not developed in mice lacking the specific PKC isoform. This study identified the presence of ongoing pain in mice treated with nitroglycerin, a known human migraine trigger that closely resembles the common manifestation of spontaneous migraine attacks in humans. These findings demonstrated a critical regulatory role of PKCδ in migraine pathophysiology, which may offer new pharmacological targets for anti-migraine treatment.
Learn More >A significant proportion of children/adolescents report Chronic Widespread Pain (CWP), but little is known about clinically relevant CWP or what factors lead to onset in this population. Objectives were to report the primary care consultation prevalence of CWP, and investigate risk factors associated with onset. A validated algorithm for identifying CWP status from primary care electronic healthcare records, was applied to a child/adolescent population (aged 8 to 18 years). The algorithm records patients who have recurrent pain consultations (axial skeleton and upper or lower limbs), or those with a non-specific generalised pain disorder (e.g. fibromyalgia). Prevalence was described, and a nested case-control study established to identify risk factors associated with CWP onset using logistic regression producing Odds Ratios (OR) and 95% Confidence Intervals (95%CI). 271 children/adolescents were identified with CWP, resulting in a five-year consultation prevalence of 3.19%. Risk factors significantly associated with CWP onset were; mental health (e.g. anxiety/neurosis consultations), neurological (e.g. headaches), genitourinary (e.g. cystitis), gastrointestinal (e.g. abdominal pain) and throat problems (e.g. sore throats). Children/adolescents with one or two risk factors (OR 2.15, 95% CI 1.6 to 2.9) or three or more risk factors (OR 9.17, 95% CI 5.9 to 14.3) were at significantly increased odds of CWP onset compared to those with none. Findings show a significant proportion of the child/adolescent primary care population have CWP. The majority of risk factors involved pain-related conditions, suggesting potential pathways of pain development. Further work is now needed to better understand the development of CWP in children and adolescents.
Learn More >Whilst it is clear that osteoarthritis (OA) pain involves activation and/or sensitization of nociceptors that innervate knee joint articular tissues, much less is known about the role of the innervation of surrounding bone. In this study, we used mono-iodoacetate (MIA)-induced OA in male rats to test the idea that pain in OA is driven by differential contributions from nerves that innervate knee joint articular tissues vs the surrounding bone. The time-course of pain behavior was assayed using the advanced dynamic weight bearing device, and histopathology was examined using H&E histology. Extracellular electrophysiological recordings of knee joint and bone afferent neurons were made early (day 3) and late (day 28) in the pathogenesis of MIA-induced OA. We observed significant changes in the function of knee joint afferent neurons, but not bone afferent neurons, at day 3 when there was histological evidence of inflammation in the joint capsule, but no damage to the articular cartilage or subchondral bone. Changes in the function of bone afferent neurons were only observed at day 28, when there was histological evidence of damage to the articular cartilage and subchondral bone. Our findings suggest that pain early in MIA-induced OA involves activation and sensitization of nerves that innervate the joint capsule but not the underlying subchondral bone, and that pain in late MIA-induced OA involves the additional recruitment of nerves that innervate the subchondral bone. Thus, nerves that innervate bone should be considered important targets for development of mechanism-based therapies to treat pain in late OA.
Learn More >There are few effective treatments for acute whiplash-associated disorders (WAD). Early features of central sensitisation predict poor recovery. The effect of pregabalin on central sensitisation might prevent chronic pain after acute whiplash injury. This double blind, placebo-controlled randomised controlled trial (RCT) examined feasibility and potential effectiveness of pregabalin compared to placebo for people with acute WAD. Twenty-four participants with acute WAD (<48 hours) and at risk of poor recovery (pain ≥ 5/10) were recruited from hospital Emergency Departments in Queensland, Australia and randomly assigned by concealed allocation to either pregabalin (n=10) or placebo (n=14). Pregabalin was commenced at 75 mg bd, titrated to 300 mg bd for 4 weeks, and then weaned over 1 week. Participants were assessed at 5 weeks, 3, 6 and 12 months. Feasibility issues included recruitment difficulties and greater attrition in the placebo group. For the primary clinical outcome of neck pain intensity, attrition at 5 weeks was: pregabalin: 10%, placebo: 36%, and at 12 months was: pregabalin: 10%, placebo: 43%. Pregabalin may be more effective than placebo for the primary clinical outcome of neck pain intensity at 3 months [Mean Difference: -4.0 (95% CI -6.2 to -1.7)] on an eleven point numerical rating scale. Effects were maintained at 6 but not 12 months. There were no serious adverse events. Minor adverse events were more common in the pregabalin group. A definitive large RCT of pregabalin for acute whiplash injury is warranted. Feasibility issues would need to be addressed with modifications to the protocol.
Learn More >Preclinical studies have demonstrated the analgesic potential of cannabidiol (CBD). Those suggesting an effect on pain-processing receptors have brought CBD back into focus. This study assessed the effect of CBD on acute pain, hyperalgesia, and allodynia compared with placebo. Twenty healthy volunteers were included in this randomized, placebo-controlled, double-blinded, crossover study assessing pain intensities (using numeric rating scale), secondary hyperalgesia (von Frey filament), and allodynia (dry cotton swab) in a well-established acute pain model with intradermal electrical stimulation. The authors compared the effect of 800-mg orally administered CBD on pain compared with placebo. They further examined the effect on hyperalgesia and allodynia. Cannabidiol whole blood levels were also measured. Pain ratings (mean ± SD) did not differ significantly after CBD application compared with placebo (5.2 ± 0.7 vs 5.3 ± 0.7, P-value 0.928), neither did the areas of hyperalgesia and allodynia differ significantly after CBD application compared with placebo (hyperalgesia 23.9 ± 19.2 cm2 vs 27.4 ± 17.0 cm2, P-value 0.597; allodynia 16.6 ± 13.1 cm2 vs 17.3 ± 14.1 cm2, P-value 0.884). The CBD whole blood level (median, first to third quartile) was 2.0 µg/L (1.5-5.1) 60 minutes and 5.0 µg/L (4.0-10.4) 130 minutes after CBD application. Although the oral application of 800-mg CBD failed to show a significant effect, it is important to focus future research on different dosing, routes of administration, and CBD as a part of multimodal treatment strategies before negating its effects on acute pain.
Learn More >Excess pain after visceral provocation has been suggested as a marker for chronic pelvic pain risk in women. However, few noninvasive tests have been validated that could be performed readily on youth in early risk windows. Therefore, we evaluated the validity and reliability of a noninvasive bladder pain test in 124 healthy premenarchal females (median age 11, [interquartile range 11-12]), as previously studied in adult women. We explored whether psychosocial, sensory factors, and quantitative sensory test results were associated with provoked bladder pain and assessed the relation of bladder pain with abdominal pain history. Compared with findings in young adult females (age 21 [20-28]), results were similar except that adolescents had more pain at first sensation to void (P = 0.005) and lower maximum tolerance volume (P < 0.001). Anxiety, depression, somatic symptoms, and pain catastrophizing predicted provoked bladder pain (P's < 0.05). Bladder pain inversely correlated with pressure pain thresholds (r = -0.25, P < 0.05), but not with cold pressor pain or conditioned pain modulation effectiveness. Bladder pain was also associated with frequency of abdominal pain symptoms (r = 0.25, P = 0.039). We found strong retest reliability for bladder pain at standard levels of sensory urgency in 21 adolescents who attended repeat visits at 6 to 12 months (intraclass correlations = 0.88-0.90). Noninvasive bladder pain testing seems reproducible in adolescent females and may predict abdominal pain symptomatology. Confirmation of our findings and further investigation of the bladder test across menarche will help establish how visceral sensitivity contributes to the early trajectory of pelvic pain risk.
Learn More >Peripheral sensory neurons transduce physicochemical stimuli affecting somatic tissues into the firing of action potentials that are conveyed to the central nervous system. This results in conscious perception, adaptation, and survival, but alterations of the firing patterns can result in pain and hypersensitivity conditions. Thus, understanding the molecular mechanisms underlying action potential firing in peripheral sensory neurons is essential in sensory biology and pathophysiology. Over the past 30 years, it has been consistently reported that these cells can display membrane potential instabilities (MPIs), in the form of subthreshold membrane potential oscillations or depolarizing spontaneous fluctuations. However, research on this subject remains sparse, without a clear conductive thread to be followed. To address this, we here provide a synthesis of the description, molecular bases, mathematical models, physiological roles, and pathophysiological implications of MPIs in peripheral sensory neurons. Membrane potential instabilities have been reported in trigeminal, dorsal root, and Mes-V ganglia, where they are believed to support repetitive firing. They are proposed to have roles also in intercellular communication, ectopic firing, and responses to tonic and slow natural stimuli. We highlight how MPIs are of great interest for the study of sensory transduction physiology and how they may represent therapeutic targets for many pathological conditions, such as acute and chronic pain, itch, and altered sensory perceptions. We identify future research directions, including the elucidation of the underlying molecular determinants and modulation mechanisms, their relation to the encoding of natural stimuli and their implication in pain and hypersensitivity conditions.
Learn More >Attentional bias to pain-related information may contribute to chronic pain maintenance. It is theoretically predicted that attentional bias to pain-related language derives from attentional bias to painful sensations; however, the complex interconnection between these types of attentional bias has not yet been tested. This study aimed to investigate the association between attentional bias to pain words and attentional bias to the location of pain, as well as the moderating role of pain-related interpretation bias in this association. Fifty-four healthy individuals performed a visual probe task with pain-related and neutral words, during which eye movements were tracked. In a subset of trials, participants were presented with a cold pain stimulus on one hand. Pain-related interpretation and memory biases were also assessed. Attentional bias to pain words and attentional bias to the pain location were not significantly correlated, although the association was significantly moderated by interpretation bias. A combination of pain-related interpretation bias and attentional bias to painful sensations was associated with avoidance of pain words. In addition, first fixation durations on pain words were longer when the pain word and cold pain stimulus were presented on the same side of the body, as compared to on opposite sides. This indicates that congruency between the locations of pain and pain-related information may strengthen attentional bias. Overall, these findings indicate that cognitive biases to pain-related information interact with cognitive biases to somatosensory information. The implications of these findings for attentional bias modification interventions are discussed.
Learn More >Chronic postsurgical pain (CPSP) and disability after cardiothoracic surgery are highly prevalent and difficult to treat. Researchers have explored a variety of presurgical risk factors for CPSP and disability after cardiothoracic surgery, including one study that examined distress from bodily sensations. The current prospective, longitudinal study sought to extend previous research by investigating presurgical distress about bodily sensations as a risk factor for CPSP and disability after cardiothoracic surgery while controlling for several other potential psychosocial predictors. Participants included 543 adults undergoing nonemergency cardiac or thoracic surgery who were followed over 6 months postsurgically. Before surgery, participants completed demographic, clinical, and psychological questionnaires. Six months after surgery, participants reported the intensity of CPSP on a 0 to 10 numeric rating scale and pain disability, measured by the Pain Disability Index. Multinomial logistic regression analyses were conducted to evaluate the degree to which presurgical measures predicted pain outcomes 6 months after surgery. The results showed that CPSP intensity was significantly predicted by age and presurgical scores on the Symptom Checklist-90-Revised Somatization subscale (Nagelkerke R2 = 0.27, P < 0.001), whereas chronic pain disability was only predicted by presurgical Symptom Checklist-90-Revised Somatization scores (Nagelkerke R2 = 0.29, P < 0.001). These findings demonstrate that presurgical distress over bodily sensations predicts greater chronic pain intensity and disability 6 months after cardiothoracic surgery and suggest that presurgical treatment to diminish such distress may prevent or minimize CPSP intensity and disability.
Learn More >The vasculature is innervated by a network of peripheral afferents that sense and regulate blood flow. Here, we describe a system of non-peptidergic sensory neurons with cell bodies in the spinal ganglia that regulate vascular tone in the distal arteries. We identify a population of mechanosensitive neurons, marked by tropomyosin receptor kinase C (TrkC) and tyrosine hydroxylase in the dorsal root ganglia, which projects to blood vessels. Local stimulation of TrkC neurons decreases vessel diameter and blood flow, whereas systemic activation increases systolic blood pressure and heart rate variability via the sympathetic nervous system. Ablation of the neurons provokes variability in local blood flow, leading to a reduction in systolic blood pressure, increased heart rate variability, and ultimately lethality within 48 h. Thus, a population of TrkC sensory neurons forms part of a sensory-feedback mechanism that maintains cardiovascular homeostasis through the autonomic nervous system.
Learn More >To review the contemporary issues of healthcare disparities in Headache Medicine with regard to race/ethnicity, socioeconomic status and geography and propose solutions for addressing these disparities.
Learn More >Inflammation plays a key role in the progression and maintenance of chronic pain, which impacts the lives of millions of Americans. Despite growing evidence that chronic pain can be improved by treating underlying inflammation, successful treatments are lacking and pharmaceutical interventions are limited due to drug side effects. Here we are testing whether a 'healthy human' diet (HHD), with or without anti-inflammatory components (HHAID), improves pain-like behaviors in a preclinical model of chronic widespread hypersensitivity induced by neonatal maternal separation (NMS). The HHD and HHAID are isocaloric and macronutrient-matched, have a low glycemic index, and fat content (35 kcal%) that is high in omega-3 fatty acids, while only the HHAID includes a combination of key anti-inflammatory compounds, at clinically relevant doses. Mice on these diets were compared to mice on a control diet with a macronutrient composition commonly used in rodents (20% protein, 70% carbohydrate, 10% fat). Our results demonstrate a benefit of the HHAID on pain-like behaviors in both male and female mice, despite increased caloric intake, adiposity, and weight gain. In female mice, HHAID specifically increased measures of metabolic syndrome and inflammation compared to the HHD and control diet groups. Male mice were susceptible to worsening metabolic measures on both the HHAID and HHD. This work highlights important sexual dimorphic outcomes related to early life stress exposure and dietary interventions, as well as a potential disconnect between improvements in pain-like behaviors and metabolic measures.
Learn More >Adult rats that experienced neonatal limited bedding (NLB), a form of early-life stress, experience persistent muscle mechanical hyperalgesia. Since there is a growing recognition that the gut microbiome regulates pain and nociception, and that early-life stress produces a long-lasting impact on the gut microbiome, we tested the hypothesis that persistent muscle hyperalgesia seen in adult NLB rats could be ameliorated by interventions that modify the gut microbiome. Adult NLB rats received probiotics, either GG (10 billion CFU/150 ml) or De Simone Formulation (DSF) (112.5 billion CFU/150 ml mixture of 8 bacterial species), in their drinking water, or non-absorbable antibiotics, rifaximin or neomycin, admixed with cookie dough, to provide 50 mg/kg. Mechanical nociceptive threshold in the gastrocnemius muscle was evaluated before and at several time points after administration of probiotics or antibiotics. Adult NLB rats fed probiotics or DSF, antibiotics, as well as rats fed non-absorbable antibiotics rifaximin or neomycin, had markedly attenuated muscle mechanical hyperalgesia. We hypothesize that persistent skeletal muscle hyperalgesia produced by NLB stress may be, at least in part, due to a contribution of the gut microbiome, and that modulation of gut microbiome using probiotics or non-absorbable antibiotics, may be novel therapeutic approaches for the treatment of chronic musculoskeletal pain.
Learn More >Migraine is a common but poorly understood sensory circuit disorder. Mouse models of familial hemiplegic migraine (FHM, a rare monogenic form of migraine with aura) show increased susceptibility to cortical spreading depression (CSD, the phenomenon that underlies migraine aura and can activate migraine headache mechanisms), allowing an opportunity to investigate the mechanisms of CSD and migraine onset. In FHM type 2 (FHM2) knock-in mice with reduced expression of astrocytic Na, K-ATPases, the reduced rate of glutamate uptake into astrocytes can account for the facilitation of CSD initiation. Here, we investigated the underlying mechanisms and show that the reduced rate of glutamate clearance in FHM2 mice results in increased amplitude and slowing of rise time and decay of the NMDA receptor (NMDAR) excitatory postsynaptic current (EPSC) elicited in layer 2/3 pyramidal cells by stimulation of neuronal afferents in somatosensory cortex slices. The relative increase in NMDAR activation in FHM2 mice is activity-dependent, being larger after high-frequency compared to low-frequency afferent activity. Inhibition of GluN1-N2B NMDARs, which hardly affected the NMDAR EPSC in wild-type mice, rescued the increased and prolonged activation of NMDARs as well as the facilitation of CSD induction and propagation in FHM2 mice. Our data suggest that the enhanced susceptibility to CSD in FHM2 is mainly due to specific activation of extrasynaptic GluN1-N2B NMDARs and point to these receptors as possible therapeutic targets for prevention of CSD and migraine.
Learn More >Mast cell (MC) activation could establish a positive feedback loop that perpetuates inflammation and maintains pain. Stabilizing MCs with ketotifen fumarate (KF) may disrupt this loop and relieve pain.
Learn More >Individuals with chronic low back pain (cLBP) frequently report sleep disturbances. Living in a neighborhood characterized by low-socioeconomic status (SES) is associated with a variety of negative health outcomes, including poor sleep. Whether low-neighborhood SES exacerbates sleep disturbances of people with cLBP, relative to pain-free individuals, has not previously been observed. This study compared associations between neighborhood-level SES, pain-status (cLBP vs. pain-free), and daily sleep metrics in 117 adults (cLBP = 82, pain-free = 35). Neighborhood-level SES was gathered from Neighborhood Atlas, which provides a composite measurement of overall neighborhood deprivation (e.g. area deprivation index). Individuals completed home sleep monitoring for 7-consecutive days/nights. Neighborhood SES and pain-status were tested as predictors of actigraphic sleep variables (e.g., sleep efficiency). Analyses revealed neighborhood-level SES and neighborhood-level SES*pain-status interaction significantly impacted objective sleep quality. These findings provide initial support for the negative impact of low neighborhood-level SES and chronic pain on sleep quality.
Learn More >To investigate the bidirectional association between migraine and rheumatoid arthritis (RA).
Learn More >Fibromyalgia is a centralized multidimensional chronic pain syndrome, but its pathophysiology is not fully understood.
Learn More >Fremanezumab is a humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide and is approved in Europe for migraine prevention in adults with ≥4 migraine days/month. The Pan-European Real Life (PEARL) study is a 24-month, prospective, observational study of fremanezumab in chronic or episodic migraine. End points include proportion of patients with ≥50% reduction in monthly migraine days during 6 months of treatment (primary); changes in monthly migraine days, disability scores and acute headache medication use; adherence and persistence; and effectiveness in patients switching from another calcitonin gene-related peptide pathway-targeting monoclonal antibody. PEARL is being conducted in approximately 100 centers in 11 European countries (estimated n = 1100). PEARL will generate important real-world data on effectiveness of fremanezumab and treatment patterns in patients with chronic migraine or episodic migraine.
Learn More >To assess the prevalence of antiplexin D1 antibodies (plexin D1-immunoglobulin G [IgG]) in small fiber neuropathy (SFN) and the effects of these antibodies in vivo.
Learn More >Ketamine, an anesthetic adjunct, is routinely administered as part of a balanced general anesthetic technique. We recently showed that the acute analgesic and dissociation properties of ketamine are separable to suggest that distinct neural circuits underlie these states.
Learn More >Objective disease markers are a key for diagnosis and personalized interventions. In chronic pain, such markers are still not available, and therapy relies on individual patients' reports. However, several pain studies have reported group-based differences in functional magnetic resonance imaging, electroencephalography, and magnetoencephalography (MEG).
Learn More >One of the advantages of CGRP monoclonal antibodies is their excellent safety and tolerability. However, postmarketing surveillance, is essential to detect potential rare emergent adverse events.
Learn More >The COVID-19 pandemic has acutely challenged health systems and catalyzed the need for widescale virtual care and digital solutions across all areas of health, including pediatric chronic pain. The objective of this rapid systematic review was to identify recommendations, guidelines, and/or best practices for using virtual care to support youth with chronic pain and their families (CRD42020184498). MEDLINE, CINAHL, Embase, APA PsychINFO, and Web of Science were searched the week of May 25, 2020, for English language peer-reviewed articles published since 2010 that (1) discussed children and adolescents aged <18 years reporting any type of chronic pain (ie, pain lasting >3 months); (2) focused on any type of virtual care (eg, telephone, telehealth, telemedicine, mHealth, eHealth, online, or digital); and (3) reported on guidelines, best practices, considerations, or recommendations for virtual care. Abstract and full text screening and data extraction were performed in duplicate. Meta-ethnography was used to synthesize concepts across articles. Of 4161 unique records screened, 16 were included addressing diverse virtual care and pediatric chronic pain conditions. Four key themes were identified: (1) opportunities to better leverage virtual care, (2) direct effective implementation of virtual care, (3) selection of virtual care platforms, and (4) gaps in need of further consideration when using virtual care to support youth with chronic pain and their families. No existing guidelines for virtual care for pediatric chronic pain were identified; however, best practices for virtual care were identified and should be used by health professionals, decision makers, and policymakers in implementing virtual care.
Learn More >Recent neuroimaging evidence suggests that mindfulness practice may mitigate the biasing influence of prior cognitive and emotional expectations on pain perception. The current study tested this hypothesis using a pain-cueing paradigm, which has reliably been shown to elicit conditioned hypoalgesic and hyperalgesic effects. Specifically, we aimed to investigate whether the instructed use of a mindfulness compared to a suppression strategy differentially modulates the magnitudes of conditioned hypoalgesia and hyperalgesia.
Learn More >Several animal and human studies revealed that joint and nerve mobilisations positively influence neuroimmune responses in neuromusculoskeletal conditions. However, no systematic review and meta-analysis has been performed. Therefore, this study aimed to synthesize the effects of joint and nerve mobilisation compared with sham or no intervention on neuroimmune responses in animals and humans with neuromusculoskeletal conditions. Four electronic databases were searched for controlled trials. Two reviewers independently selected studies, extracted data, assessed the risk of bias, and graded the certainty of the evidence. Where possible, meta-analyses using random effects models were used to pool the results. Preliminary evidence from 13 animal studies report neuroimmune responses after joint and nerve mobilisations. In neuropathic pain models, meta-analysis revealed decreased spinal cord levels of glial fibrillary acidic protein, dorsal root ganglion levels of interleukin-1β, number of dorsal root ganglion nonneuronal cells, and increased spinal cord interleukin-10 levels. The 5 included human studies showed mixed effects of spinal manipulation on salivary/serum cortisol levels in people with spinal pain, and no significant effects on serum β-endorphin or interleukin-1β levels in people with spinal pain. There is evidence that joint and nerve mobilisations positively influence various neuroimmune responses. However, as most findings are based on single studies, the certainty of the evidence is low to very low. Further studies are needed.
Learn More >Previous studies have indicated a negative correlation between GRK2 expression and pain development and transmission. Here, we investigated whether G protein-coupled receptor kinase 2 (GRK2) was involved in regulating diabetic mechanical hyperalgesia (DMH).
Learn More >There have been repeated calls to re-evaluate how clinicians provide care for people presenting with persistent non-traumatic musculoskeletal conditions. One suggestion is to move away from the 'we can fix and cure you' model to adopting an approach that is more consistent with approaches used when managing other persistent non-communicable diseases; education, advice, a major focus on self-management including lifestyle behavioural change, physical activity and medications as required. Currently the global delivery of musculoskeletal care has many of the elements of a 'super wicked problem', namely conflict of interest from stake-holders due to the consequences of change, prevailing expectation of a structural diagnosis and concomitant fix for musculoskeletal pain, persistent funding of high risk, more expensive care when low risk more economic viable options that don't impact on the quality of outcome exist, and an unquestionable need to find a solution now with the failure resulting in a growing social and economic burden for future generations. To address these issues, 100 participants included clinicians, educators and researchers from low-, middle- and high-income countries, eight presenters representing the physiotherapy, sport medicine and the orthopaedic professions and the insurance industry, together with three people who shared their lived experiences of persistent musculoskeletal pain, discussed the benefits and barriers of implementing change to address this problem. This paper presents the results from the stakeholders' contextual analysis and forms the basis for the proposed next steps from an action and advocacy perspective.
Learn More >Quantitative objective measurement of chronic pain is important. We elucidated chronic pain-related cortical neural activity and neural connectivity among pain-related brain regions in complex regional pain syndrome (CRPS). Resting-state magnetoencephalography recordings were performed. Cortical current density and neural connectivity, revealed by amplitude envelope correlation (AEC), were estimated on standardized brain magnetic resonance imaging. Intra-experiment pain was assessed subjectively using a visual analogue scale (VAS). The correlation between current density and VAS scores was calculated for the occipital areas and pain-related cortices. Current density in the primary (SI) and secondary (SII) somatosensory cortex and precuneus in both hemispheres was negatively correlated with the pain VAS score. The AEC and VAS values were significantly correlated for the SII and the precuneus and for the SII and insular cortex in the alpha frequency band in the right hemisphere. In the theta frequency band, the AEC and VAS values correlated for the SII and posterior cingulate cortex in the right hemisphere. Our results suggested that disruption of pain processes and functions in the default mode network occurs in CRPS. Our method targeting the neural mechanism of pain has the potential to offer a clinically objective means of evaluating it.
Learn More >Familial hemiplegic migraine (FHM) is an inherited autosomal dominant disorder characterized by migraine with reversible hemiplegia. FHM1 is caused by variants in CACNA1A, encoding a P/Q type neuronal voltage-gated calcium channel α subunit, which is also associated with episodic ataxia type 2 (EA2). FHM2 is associated with ATP1A2, which codes for an Na/K-ATPase isoform 2 subunit.
Learn More >Chronic pain and depression are two frequently co-occurring and debilitating conditions. Even though the former is treated as a physical affliction, and the latter as a mental illness, both disorders closely share neural substrates. Here, we review the association of pain with depression, especially when symptoms are lateralized on either side of the body. We also explore the overlapping regions in the forebrain implicated in these conditions. Finally, we synthesize these findings into a model, which addresses gaps in our understanding of comorbid pain and depression. Our lateralized pain-depression dyad model suggests that individuals diagnosed with depression should be closely monitored for pain symptoms in the left hemibody. Conversely, for patients in pain, with the exception of acute pain with a known source, referrals in today's pain centers for psychological evaluation should be part of standard practice, within the framework of an interdisciplinary approach to pain treatment.
Learn More >Hereditary sensory neuropathies (HSN) are a group of rare neurological disorders with heterogeneous clinical and genetic characteristics. Although at least 17 different genes have already been associated with HSN, the epidemiology of the disorder in Brazil is still unknown. Performing whole genome sequencing (WGS) in 23 unrelated Brazilian families diagnosed with HSN, we detected pathogenic variants in ATL3, SPTLC2, and SCN9A in 12 patients belonging to five unrelated families. Clinical features associated with heterozygous mutations in ATL3 (c.575A > G; p.(Tyr192Cys)) and SPTLC2 (c.529A > G; p.(Asn177Asp)) were sensory deficits, neuropathic pain, and recurrent ulcerations. Presenting as congenital insensitivity to pain, three unrelated probands carried biallelic loss-of-function mutations in SCN9A. The so far undescribed stop mutation c.2106G > A (p.(Trp702Ter)) and the likewise novel splicing variant c.3319-1G > A were found in compound-heterozygosity with, respectively, the known pathogenic variants c.2908G > T (p.Trp970Ter) and c.2690G > A (p.Glu897Ter). In total, we identified pathogenic mutations in 21.7% of our families, which suggests that most of the cases could be explained by yet to be discovered genes or unusual alleles. Our study represents the first mutational screen in a Brazilian HSN cohort, enabling additional insights for genotype-phenotype correlations, reducing misdiagnoses, and providing early treatment considerations.
Learn More >Chronic pain is a distressing condition and often poorly treated and managed. Psychological therapies are considered first-line intervention for people with chronic pain. Common psychological therapies require extensive clinician training and specialist qualifications. One approach that does not need lengthy training nor specialist qualification, but has empirical support in other health domains, is behavioural activation (BA). BA seeks to increase engagement in behaviours that are valued by the person and progress through behaviours that can increase mood and develop skills that build satisfying routines. BA can help people to manage their condition through scheduling behaviours, promoting routine and mastery over their condition. The extent to which BA has been used to support people living with chronic pain is not clear.
Learn More >Cortical long-term potentiation (LTP) serves as a cellular model for chronic pain. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical LTP in the anterior cingulate cortex (ACC). Genetic deletion of AC1 or pharmacological inhibition of AC1 blocked behavioral allodynia in animal models of neuropathic and inflammatory pain. Our previous experiments have identified a lead candidate AC1 inhibitor, NB001, which is highly selective for AC1 over other AC isoforms, and found that NB001 is effective in inhibiting behavioral allodynia in animal models of chronic neuropathic and inflammatory pain. However, previous experiments were carried out in adult male animals. Considering the potential gender difference as an important issue in researches of pain and analgesia, we investigated the effect of NB001 in female chronic pain animal models. We found that NB001, when administered orally, has an analgesic effect in female animal models of neuropathic and inflammatory pain without any observable side effect. Genetic deletion of AC1 also reduced allodynia responses in models of neuropathic pain and chronic inflammation pain in adult female mice. In brain slices of adult female mice, bath application of NB001(20 μM) blocked the induction of LTP in ACC. Our results indicate that calcium-stimulated AC1 is required for injury-related cortical LTP and behavioral allodynia in both sexes of adult animals, and NB001 can be used as a potential therapeutic drug for treating neuropathic and inflammatory pain in man and woman.
Learn More >For neuropathic pain, current therapies do not provide relief for most patients; less than half achieve a 50% pain reduction. Current analgesics have adverse effects. We present 2 Phase I studies of LX9211, a new small-molecule AP2-associated kinase 1 inhibitor with preclinical effectiveness in pain relief.
Learn More >Migraine shows a significantly higher prevalence in women, especially during reproductive age when menstrual-related hormonal fluctuations represent the most common migraine trigger. Indeed, over 50% of patients report a higher occurrence of migraine attacks during the perimenstrual window. Menstrual migraine attacks are consistently referred to as more disabling, less responsive to symptomatic treatments, longer in duration, and more prone to relapse than non-menstrual migraine attacks. Evidence strongly suggests that estrogen fluctuations are involved in migraine attacks worsening during the perimenstrual window through several mechanisms directly or indirectly involving the CGRP pathway. We aimed to evaluate whether mAbs blocking CGRP-ligand or receptor (CGRP-mAbs) could represent an effective and safe preventive treatment for menstrual migraine attacks in patients with menstrual-related migraine (MRM) with previous treatment failures.
Learn More >To assess the impacts of social situation changes due to the coronavirus disease 2019 (COVID-19) pandemic on headache-related disability and other symptoms in patients with migraine in Japan.
Learn More >Risk assessment tools can improve clinical decision-making for individuals with musculoskeletal pain, but do not currently exist for predicting reduction of pain intensity as an outcome from physical therapy.
Learn More >To assess the long-term outcome of breast reconstructions with special focus on chronic postsurgical pain (CPSP) in a larger cohort of breast cancer survivors.
Learn More >Chronic low back pain or chronic cervical pain often has a neuropathic pain (NeP) component and patients with these conditions complain of sleep deprivation, loss of physical function, and reduced productivity due to pain. The objective of this study was to clarify the pathway by which pain, sleep disturbance due to pain, and physical function status influence QOL measures in chronic low back pain patients with NeP associated with lumbar spine diseases (CLBP-NeP) and in chronic cervical pain patients with NeP associated with cervical spine diseases (CCP-NeP).
Learn More >Obesity is one of the most prevalent comorbidities associated with chronic pain, which can severely interfere with daily living and increase utilization of clinical resources. We hypothesized that a higher level of obesity, measured by BMI, would be associated with increased pain severity (intensity) and interference (pain related disability). Participant data was pulled from a multisite chronic pain outpatient database and categorized based on BMI. A total of 2509 patients were included in the study. We found significant differences between BMI groups for all pain severity scores (worst, least, average, current) and total pain interference score. Obese patients had significantly higher scores than normal weight patients. We found obesity to be associated with increased pain severity and pain interference.
Learn More >Spinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown.
Learn More >This study was designed to explore the efficacy and feasibility of cognitive behavioural therapy(CBT) along with pregabalin and compare it with pregabalin monotherapy for the management of neuropathic pain in post-herpetic neuralgia (PHN) patients and to explore the modulation of mRNA expression of interleukin (IL)-6 and mammalian target of rapamycin-1 (mTORC1) genes in these patients.
Learn More >The COVID-19 pandemic has spurred a hasty transition to virtual care but also an abundance of new literature highlighting telehealth's capabilities and limitations for various healthcare applications. In this review, we aim to narrate the current state of the literature on telehealth applied to migraine care. First, telemedicine in the context of non-acute headache management has been shown to produce non-inferior patient outcomes when compared to traditional face-to-face appointments. The assignment of patients to telehealth appointments should be made after referring more urgent cases to dedicated in-person clinics. During the virtual appointment, physicians can ask their patients about the "3 F's" in order to perform a thorough assessment of their headaches: frequency of headache days, frequency of acute medication usage and functional impairment. Clinical assessment scores that have been studied and deemed feasible for telemedicine, safe and efficient include the HIT-6, VAS and MIDAS scores. Although MIDAS was found to be redundant and inadequate to use on a daily basis, we suggest that it can be useful in periodic remote follow-up appointments. Additionally, several mobile health apps have been studied including Migraine Buddy, Migraine Coach and Migraine Monitor. All of these are appropriate for use in telemedicine when combined with an adequate trial period with Migraine Buddy being rated the highest, as it captures the most detailed clinical picture. High satisfaction rates have been reported for virtual headache management which were shown to be equal to in-person consults. These are based on patients' perceived increase in convenience due to avoided travel time, less disruption of their daily routine and feeling more comfortable in the environment of their choice. Despite this, limitations such as technological knowledge, access to videoconferencing modalities and having a more impersonal consultation with the physician may hinder some patients from adopting this service.
Learn More >Opioids are a commonly prescribed and efficacious medication for the treatment of chronic pain but major side effects such as addiction, respiratory depression, analgesic tolerance, and paradoxical pain hypersensitivity make them inadequate and unsafe for patients requiring long-term pain management. This review summarizes recent advances in our understanding of the outcomes of chronic opioid administration to lay the foundation for the development of novel pharmacological strategies that attenuate opioid tolerance and hypersensitivity; the two main physiological mechanisms underlying the inadequacies of current therapeutic strategies. We also explore mechanistic similarities between the development of neuropathic pain states, opioid tolerance, and hypersensitivity which may explain opioids' lack of efficacy in certain patients. The findings challenge the current direction of analgesic research in developing non-opioid alternatives and we suggest that improving opioids, rather than replacing them, will be a fruitful avenue for future research.
Learn More >Research has shown that opioid craving is one of the strongest determinants of opioid misuse in patients with chronic pain. To date, however, little is known on the factors that contribute to opioid craving in these patients. It is possible that patients' physical dependence to opioids, manifested by opioid withdrawal symptoms in between daily opioid doses, contribute to opioid craving. Physical dependence symptoms might also lead to psychological distress, which in turn might contribute to opioid craving. The first objective of this study was to examine the day-to-day association between opioid withdrawal symptoms and opioid craving among patients with chronic pain. We also examined whether negative affect and catastrophic thinking mediated this association.
Learn More >The pathogeneses of chronic tension-type headache (CTTH) and cervicogenic headache (CEH) are not well established. Peripheral activation or sensitization of myofascial nociceptors is suggested as a potential mechanism and injections of botulinum toxin (BONTA) have thus been used in the treatment for both headache conditions. BONTA inhibits the release of acetylcholine at the neuromuscular junction and inhibits contraction of skeletal muscles. If the pain is precipitated by increased tone in cervical muscles, local injections of BONTA could represent a prophylactic measure. However, the treatment is still controversial, and a thorough assessment of the current evidence is required. This review aims to assess the evidence of BONTA injection as a prophylactic treatment for CTTH and CEH by reviewing and examining the quality of placebo-controlled, randomized trials.
Learn More >Limited cohort studies have assessed the association between uncontrolled pain and risk for behavioral and psychological symptoms of dementia (BPSDs). We conducted a longitudinal cohort study to examine whether associations exist between uncontrolled pain and risk for 2 common BPSDs-depression and behavioral symptoms-among long-term care (LTC) residents with Alzheimer disease and related dementia (ADRD).
Learn More >Trigeminal neuralgia, a severe chronic neuropathic pain disorder, is widely believed to be amenable to surgical treatments. Nearly 20% of patients, however, do not have adequate pain relief after surgery. Objective tools for personalized pre-treatment prognostication of pain relief following surgical interventions can minimize unnecessary surgeries and thus are of substantial benefit for patients and clinicians.
Learn More >Cancer-related neuropathic pain (CNP) affects an increasing proportion of cancer patients given improved survival but remains difficult to treat. There are no studies on an extended intravenous (IV) ketamine protocol and its synergies with common neuropathy treatments to treat CNP. This study aims to (1) evaluate the safety and effectiveness of an IV ketamine protocol to treat refractory CNP and (2) uncover synergies between ketamine and common neuropathy treatments.
Learn More >There is accumulating evidence of the neurological and neuropsychiatric features of infection with SARS-CoV-2. In this systematic review and meta-analysis, we aimed to describe the characteristics of the early literature and estimate point prevalences for neurological and neuropsychiatric manifestations.We searched MEDLINE, Embase, PsycINFO and CINAHL up to 18 July 2020 for randomised controlled trials, cohort studies, case-control studies, cross-sectional studies and case series. Studies reporting prevalences of neurological or neuropsychiatric symptoms were synthesised into meta-analyses to estimate pooled prevalence.13 292 records were screened by at least two authors to identify 215 included studies, of which there were 37 cohort studies, 15 case-control studies, 80 cross-sectional studies and 83 case series from 30 countries. 147 studies were included in the meta-analysis. The symptoms with the highest prevalence were anosmia (43.1% (95% CI 35.2% to 51.3%), n=15 975, 63 studies), weakness (40.0% (95% CI 27.9% to 53.5%), n=221, 3 studies), fatigue (37.8% (95% CI 31.6% to 44.4%), n=21 101, 67 studies), dysgeusia (37.2% (95% CI 29.8% to 45.3%), n=13 686, 52 studies), myalgia (25.1% (95% CI 19.8% to 31.3%), n=66 268, 76 studies), depression (23.0% (95% CI 11.8% to 40.2%), n=43 128, 10 studies), headache (20.7% (95% CI 16.1% to 26.1%), n=64 613, 84 studies), anxiety (15.9% (5.6% to 37.7%), n=42 566, 9 studies) and altered mental status (8.2% (95% CI 4.4% to 14.8%), n=49 326, 19 studies). Heterogeneity for most clinical manifestations was high.Neurological and neuropsychiatric symptoms of COVID-19 in the pandemic's early phase are varied and common. The neurological and psychiatric academic communities should develop systems to facilitate high-quality methodologies, including more rapid examination of the longitudinal course of neuropsychiatric complications of newly emerging diseases and their relationship to neuroimaging and inflammatory biomarkers.
Learn More >Wearable electronic devices are a convenient solution to pain intensity assessment as they can provide continuous monitoring for more precise medication adjustments. However, there is little evidence regarding the use of wearable electronic devices for chronic pain intensity assessment. Our primary objective was to examine the physiologic parameters used by wearable electronic devices for chronic pain intensity assessment. We initially inquired PubMed, CINAHL, and Embase for studies evaluating the use of wearable electronic devices for chronic pain intensity assessment. We updated our inquiry by searching on PubMed, Embase, Scopus, and Google Scholar. English peer-reviewed studies were included, with no exclusions based on time frame or publication status. Of 348 articles that were identified on the first inquiry, 8 fulfilled the eligibility criteria. Of 179 articles that were identified on the last inquiry, 1 fulfilled the eligibility criteria. We found articles evaluating wristbands, smartwatches, and belts. Parameters evaluated were psychomotor and sleep patterns, space and time mobility, heart rate variability, and skeletal muscle electrical activity. Most of the studies found significant positive associations between physiological parameters measured by wearable electronic devices and self-reporting pain scales. Wearable electronic devices reliably reflect physiologic or biometric parameters, providing a physiological correlation for pain. Early-stage investigation suggests that the degree of pain intensity can be discerned, which ideally will reduce the bias inherent to existing numeric/verbal scales. Further research on the use of these devices is vital.
Learn More >Over the past year our attention has inevitably been on the coronavirus pandemic, the health and welfare of our families, patients, and office staffs as well as the re-opening of our dental practices. In addition, the opioid crisis continues, is very likely to worsen as a result of the pandemic and continues to be a challenge to Dentistry. National public health issues and healthcare disparities continue and have created a global concern for providing evidence-based, adequate pain management in the dental setting. We have brought together a group of national thought leaders and experts in this field who will share their insights on the current state of opioid prescribing in Dentistry and describe some of the exciting work being done in advancing pain management. The learning objectives for this conference proceedings were: Describing the implications of current public health concerns for safe and effective pain management in dental medicine.Identifying risk factors and understanding the current guidelines for the use of opioid and non-opioid medications in dental medicine.Analyzing the interprofessional collaborations necessary for effective pain management in dental medicine.Recognizing the challenges and opportunities brought about by the COVID-19 pandemic for the dental profession.Applying evidence-based strategies for managing the complex pain patient in the dental setting.Appraising new and future modalities for the assessment and management of orofacial pain.
Learn More >To assess the validity and reliability of the self-administered Visual Aura Rating Scale (VARS) questionnaire using a hospital-based sample in a cross-sectional setting.
Learn More >This study aimed to evaluate the effects of repeated bimodal transcranial direct current stimulation (tDCS) on alcohol consumption and immunohistological and neurochemical parameters in nerve-injured rats. Forty-eight adult male Wistar rats were distributed into six groups: control, neuropathic pain (NP)+sham-tDCS, NP+alcohol+sham-tDCS, alcohol+sham-tDCS, alcohol+tDCS, and NP+alcohol+tDCS. NP is induced by chronic sciatic nerve constriction (CCI). The rats were exposed to a 10% alcohol solution by voluntary consumption for 14 days. From the 16 day after surgery, bimodal tDCS was applied for 20 minutes/day for 8 days. Brain structures were collected to evaluate the number of neuropeptide Y (NPY)-positive neurons, neurites, and argyrophilic grains by immunohistochemistry, and brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), interleukin (IL)-6, and IL-10 by ELISA. Nerve-injured rats showed a progressive increase in alcohol consumption compared to the non-injured rats. In addition, there was a reduction in voluntary alcohol consumption over time induced by tDCS. Alcohol exposure, chronic pain, and tDCS treatment modulated the central NPY immunoreactivity. tDCS increased the cerebellar levels of IL-6 and IL-10, and CCI and/or tDCS reduced striatal BDNF levels. The current data suggest that tDCS could be a promising non-pharmacological adjuvant to treat patients with chronic pain who use alcohol to relieve their symptoms.
Learn More >Sleep health is an important factor across several physical and mental health disorders, and a growing scientific consensus has identified sleep as a critical component of opioid use disorder (OUD), both in the active disease state and during OUD recovery. The goal of this narrative review is to collate the literature on sleep, opioid use, and OUD as a means of identifying therapeutic targets to improve OUD treatment outcomes. Sleep disturbance is common and often severe in persons with OUD, especially during opioid withdrawal, but also in persons on opioid maintenance therapies. There is ample evidence that sleep disturbances including reduced total sleep time, disrupted sleep continuity, and poor sleep quality often accompany negative OUD treatment outcomes. Sleep disturbances are bidirectionally associated with several other factors related to negative treatment outcomes, including chronic stress, stress reactivity, low positive affect, high negative affect, chronic pain, and drug craving. This constellation of outcome variables represents a more comprehensive appraisal of the quality of life and quality of recovery than is typically assessed in OUD clinical trials. To date, there are very few clinical trials or experimental studies aimed at improving sleep health in OUD patients, either as a means of improving stress, affect, and craving outcomes, or as a potential mechanistic target to reduce opioid withdrawal and drug use behaviors. As such, the direct impact of sleep improvement in OUD patients is largely unknown, yet mechanistic and clinical research suggests that therapeutic interventions that target sleep are a promising avenue to improve OUD treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Learn More >Dexmedetomidine (DEX), a selective α adrenergic receptor (α-AR) agonist, has been shown to have peripheral analgesic effects in a variety of pain conditions. However, the precise molecular mechanisms have not yet been fully elucidated. Acid sensing ion channels (ASICs) are the major player in pain associated with tissue acidosis. Given that both α-ARs and ASICs exist in dorsal root ganglia (DRG) neurons, we therefore investigated the effects of DEX on the functional activity of ASICs. Herein, whole-cell patch-clamp recordings demonstrated that DEX suppressed ASIC-mediated and acid-evoked currents and action potentials in dissociated rat DRG neurons. DEX shifted downwards concentration-response curve to protons, with a decrease of 35.83 ± 3.91% in the maximal current response to pH 4.5. DEX-induced inhibition of ASIC currents was blocked by the α-AR antagonist BRL44408 in DRG neurons. DEX also inhibited ASIC3 currents in CHO cells co-expressing ASIC3 and α-ARs, but not in ASIC3 transfected CHO cells without α-ARs expression. DEX-induced inhibition of ASIC currents was mimicked by the protein kinase A inhibitor H-89, and blocked by intracellular application of the G protein inhibitor pertussis toxin and the cAMP analog 8-Br-cAMP. In addition, peripherally administration of DEX dose-dependently relieved nociceptive responses to intraplantar injection of acetic acid in rats through local α-ARs. Our results indicated that DEX inhibited the functional activity of ASICs via α-ARs and intracellular G proteins and cAMP/protein kinase A signaling pathway in rat DRG neurons, which was a novel potential mechanism that probably mediated peripheral analgesia of DEX.
Learn More >Evidence is limited on the risk impact of body pain on future chronic disease. The present study aimed to investigate the association between body pain and chronic diseases.
Learn More >Headaches are a common symptom in children. Children with refractory headaches may be admitted for inpatient treatment with intravenous dihydroergotamine mesylate (DHE). However, very few studies have characterized these patients and their treatment outcomes using validated, self-reported, pain scales.
Learn More >Migraine is a chronic neurological disorder characterized by attacks of moderate or severe headache and various neurological symptoms. Migraine is typically treated by pharmacological or non-pharmacological therapies to relieve pain or prevent migraine attacks. Pharmacological therapies show limited efficacy in relieving headache and are often accompanied by adverse effects, while the benefits of acupuncture, a non-pharmacological therapy, have been well-documented in both the treatment and prevention of acute migraine attacks. However, the underlying mechanism of the effect of acupuncture on relieving migraine remains unclear. Recent advances in neuroimaging technology have offered new opportunities to explore the underlying neural mechanism of acupuncture in treating migraine. To pave the way for future research, this review provides an overview neuroimaging studies on the use of acupuncture for migraine in the last 10 years. Using search terms about acupuncture, neuroimaging and migraine, we searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure from January 2009 to June 2020 for neuroimaging studies that examined the effect of acupuncture in migraine. All published randomized and non-randomized controlled neuroimaging studies were included. We summarized the proposed neural mechanism underlying acupuncture analgesia in acute migraine, and the proposed neural mechanism underlying the sustained effect of acupuncture in migraine prophylaxis. A total of 619 articles were retrieved. After removing reviews, meta-analyses, animal studies and etc., 15 articles were eligible and included in this review. The methods used were positron emission computed tomography (PET-CT; = 2 studies), magnetic resonance spectroscopy ( = 1), and functional magnetic resonance imaging (fMRI; = 12). The analyses used included the regional homogeneity (ReHo) method (n = 3), amplitude of low frequency (ALFF) method ( = 2), independent component analysis (ICA; = 3), seed-based analysis (SBA; = 1), both ICA and SBA ( = 1), Pearson's correlation to calculate functional connectivity (FC) between brain regions ( = 1), and a machine learning method ( = 1). Five studies focused on the instant effect of acupuncture, and the research objects were those with acute migraine ( = 2) and migraine in the interictal phase ( = 3). Ten studies focused on the lasting effect of acupuncture, and all the studies selected migraine patients in the interictal phase. This review included five task-based studies and 10 resting-state studies. None of the studies conducted a correlation analysis between functional brain changes and instant clinical efficacy. For studies that performed a correlation analysis between functional brain changes and sustained clinical efficacy, the prophylactic effect of acupuncture on migraine might be through regulation of the visual network, default mode network (DMN), sensory motor network, frontoparietal network (FPN), limbic system, and/or descending pain modulatory system (DPMS). The neural mechanism underlying the immediate effect of acupuncture analgesia remains unclear, and the neural mechanism of sustained acupuncture treatment for migraine might be related to the regulation of pain-related brain networks. The experimental design of neuroimaging studies that examined the effect of acupuncture in migraine also have some shortcomings, and it is necessary to standardize and optimize the experimental design. Multi-center neuroimaging studies are needed to provide a better insight into the neural mechanism underlying the effect of acupuncture on migraine. Multi-modality neuroimaging studies that integrate multiple data analysis methods are required for cross-validation of the neuroimaging results. In addition, applying machine learning methods in neuroimaging studies can help to predict acupuncture efficacy and screen for migraineurs for whom acupuncture treatment would be suitable.
Learn More >Indomethacin is a nonsteroidal anti-inflammatory drug whose mechanism of action in certain types of headache disorders remains unknown. The so-called indomethacin-responsive headache disorders consist of a group of conditions with a very different presentation that have a particularly good response to indomethacin. The response is so distinct as to be used in the definition of two: hemicrania continua and paroxysmal hemicrania.
Learn More >To explore medical diagnostic testing of new cases of musculoskeletal (MSK) conditions associated with chronic pain.
Learn More >To compare impact of symptoms, and healthcare utilisation, of people diagnosed with fibromyalgia, people who fulfil criteria not diagnosed and people with chronic pain.
Learn More >The aim of this article is to describe the consensus process used to develop an acupuncture intervention protocol for an NIH-funded pragmatic randomized controlled trial (PRCT) of acupuncture for the management of chronic low back (cLBP) in older adults (BackInAction).
Learn More >To evaluate the effectiveness of low-intensity focused ultrasound (LIFU) therapy in the management of cancer-related neuropathic pain (CNP). A retrospective review with 22 patients with CNP treated with LIFU therapy (frequency 3 Hz, 3 W/cm, pulse mode duty cycle 50%) was conducted. Out of the 22 patients, 15 had CNP secondary to chemotherapy-induced peripheral neuropathy. Compared with baseline, there was a significant reduction in numeric pain rating scale (p < 0.001). Additionally, 76.5% of patients (n = 13) were considered to be responders to LIFU therapy. LIFU therapy may be a viable treatment modality in the management of CNP, specifically chemotherapy-induced peripheral neuropathy, with a minimal side effect profile. Larger, prospective studies with a structured protocol are necessary.
Learn More >Dissemination research is the study of distributing information and intervention materials to a specific clinical practice or public health audience. Acupuncture, a healthcare practice involving the stimulation of certain body points, often with thin needles, is considered an evidence-based treatment for low back pain (LBP), but is underutilized in the United States. We will use the example of acupuncture for LBP to identify opportunities to leverage dissemination research to increase utilization of acupuncture. Deficits in the awareness or knowledge of acupuncture may limit its adoption by patients and other stakeholders. Thus, we summarize methods to gather data on stakeholder awareness and knowledge of acupuncture for LBP, i.e., audience research. Engaging multiple stakeholder audiences (e.g., health system leaders, primary care providers, patients), is needed to generate knowledge on promising dissemination strategies for each audience. Audience segmentation is important for identifying population subgroups for whom adoption of acupuncture may require a more intensive or tailored dissemination strategy. To illustrate potential audience 'segments', our research discussion focused on developing dissemination strategies by age (i.e., older adults – those age 65 years or older, and younger adults – those under age 65 ). This decision was prompted by Medicare's recent policy covering acupuncture for chronic LBP. We leverage current knowledge of barriers and facilitators of acupuncture use to discuss how further tailoring of dissemination strategies might optimize adoption of acupuncture in both groups of adults. Experimental study designs could then be used to compare the effectiveness of such strategies to increase awareness, knowledge, or adoption of acupuncture. Conducting dissemination research may improve awareness and knowledge of acupuncture, and ultimately the adoption of acupuncture in biomedical settings. We anticipate that the concepts highlighted in this manuscript will also be helpful for those disseminating information about other complementary and integrative health approaches.
Learn More >Although diet is an essential aspect of human health, the link between diet and pain is still not well understood. Preclinical animal research provides information to understand underlying mechanisms that allow identifying the needs for human research.
Learn More >Although there have been many magnetic resonance spectroscopy (MRS) studies of migraine, few have focused on migraines during an attack. Here, we aimed to assess metabolite changes in the brain of patients with migraine, both during an attack and in the interictal phase. Six patients (one man and five women, mean age: 39 ± 10 years) with migraine without aura during the attack (MWoA-DA), 13 patients (three men and 10 women, mean age: 31 ± 9 years) with migraine without aura during the interictal period (MWoA-DI), and 13 healthy controls (HC) (four men and nine women, mean age: 31 ± 9 years) were studied. All subjects underwent an MRS examination focusing on the occipital lobe. Metabolite changes were investigated among three groups. The MWoA-DA patients had lower glutathione/total creatine ratio (GSH/tCr) than the MWoA-DI patients and HC. Furthermore, MWoA-DI patients showed lower total choline/total creatine ratio (tCho/tCr) than those in the other two groups. The GSH/tCr ratio was positively correlated with attack frequency in the MWoA-DI group. The tCho/tCr ratio was positively correlated with attack frequency and Migraine Disability Assessment Scale (MIDAS) scores in the MWoA-DA group. The present study suggests the existence of distinct pathophysiological states between the MWoA-DA and MWoA-DI groups. Neuronal dysfunction is a possible predisposing factor for migraine attack onset, along with oxidative stress and inflammation.
Learn More >Cognition is defined as the brain's ability to acquire, process, store, and retrieve information. Pain has been described as an unpleasant sensory or emotional experience, and for experiencing pain consciously, cognitive processing becomes imperative. Moreover, evaluation of pain strongly depends on cognition as it requires learning and recall of previous experiences. There could be a possible close link between neural systems involved in cognition and pain processing, and studies have reported an association between pain and cognitive impairment. In this narrative review, we explore the available evidence that has investigated cognitive changes associated with pain. We also examine the anatomical, biochemical, and molecular association of pain and neuro-cognition. Additionally, we focus on the cognitive impairment caused by analgesic medications. There is a need to improve our understanding of pathophysiology and cognitive impairment mechanisms associated with chronic pain and its treatment. This area provides a diverse opportunity for grounding future research, aiding institution of timely interventions to prevent chronic pain and associated cognitive decline, ultimately improving patient care.
Learn More >Cluster headache (CH) is a trigeminal autonomic cephalalgia (TAC) characterized by a highly disabling headache that negatively impacts quality of life and causes limitations in daily functioning as well as social functioning and family life. Since specific measures to assess the quality of life (QoL) in TACs are lacking, we recently developed and validated the cluster headache quality of life scale (CH-QoL). The sensitivity of CH-QoL to change after a medical intervention has not been evaluated yet.
Learn More >There is growing evidence that the kynurenine pathway is involved in the pathology of diseases related to the central nervous system (CNS), because of the neuroprotective or neurotoxic properties of certain metabolites, yet the role of each metabolite is not clear. The pathology of Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) is currently under investigation, and the overlapping symptoms such as depression suggest that the CNS may be involved. These symptoms may be driven by enhanced neurotoxicity and/or diminished neuroprotection. However, the kynurenine metabolite status has not been well studied in these two possible related disorders of CFS and FM. The objective of this study was to investigate the metabolites and ratios of the kynurenine pathway in CFS and FM compared to healthy controls and examine the possible correlations with symptoms of anxiety and depression.
Learn More >Intractable migraine in children and adolescents is a significant cause of disability and decreased quality of life (QoL) in this population. Challenges include lack of unifying definition for intractable migraine, and limited data on best-practice management in this age group, with most current treatment pathways extrapolated from adult studies or expert consensus.
Learn More >Minimal clinically important difference (MCID) thresholds for a limited number of outcome metrics were previously defined for patients with failed back surgery syndrome (FBSS) at 6 months after spinal cord stimulation (SCS). This study aimed to further define MCID values for pain and disability outcomes. Additionally, the authors established 1-year MCID values for outcome measures with previously defined metrics commonly used to assess SCS efficacy.
Learn More >Post-traumatic headache is a common disorder in the pediatric age group, seen both by child neurologists and by non-neurologists. The current review of post-traumatic headache in children and adolescents aims to review the pathophysiology, risk factors, clinical features, neuroimaging, and both acute and preventive treatment options.
Learn More >Adolescent chronic pain exists within a social context, affecting the lives of adolescents, parents, peers, and wider family members. Typically, parental research has focussed on the negative impact on parents associated with parenting an adolescent with chronic pain. However, a small number of studies have identified positive parental outcomes and functioning, with a focus on parental resilience. This study sought to extend existing knowledge by providing a detailed and contextualized understanding of how parental dyads experience and demonstrate resilience in response to parenting an adolescent with Complex Regional Pain Syndrome (CRPS) and the meaning that parents ascribe to these shared experiences.
Learn More >The DSM-5 diagnostic criteria for Prescription Opioid-Use Disorder (POUD) have undergone some significant changes. One of the most controversial changes has been the elimination of the withdrawal symptoms criterion when opioid use is under appropriate medical supervision. For this reason, the goal of this study was to analyze factors associated with opioid withdrawal in patients with chronic non-cancer pain (CNCP).
Learn More >Migraine is the second-leading cause of disability worldwide. It is often characterized by attacks of severe, mostly unilateral, pulsating headache associated with symptoms such as photophobia, phonophobia, nausea, vomiting, and cutaneous allodynia. Acupuncture therapy has been used worldwide for the treatment of migraine. However, no visual bibliometric analysis has been conducted on the effects of acupuncture on migraine over the past 20 years. Therefore, this study aimed to explore the current status and trends on the use of acupuncture in the treatment of migraine from 2000 to 2020.
Learn More >Health care providers in the United States are facing challenges in selecting appropriate medication for patients with acute and chronic pain in the midst of the current opioid crisis and COVID-19 pandemic. When compared with conventional opioids, the partial µ-opioid receptor agonist buprenorphine has unique pharmacologic properties that may be more desirable for pain management. The formulations of buprenorphine approved by the US Food and Drug Administration for pain management include intravenous injection, transdermal patch, and buccal film. A comparison of efficacy and safety data from studies of buprenorphine and conventional opioids suggests that buprenorphine may be a better-tolerated treatment option for many patients that provides similar or superior analgesia. Our benefit-risk assessment in this narrative review suggests that health care providers should consider that buprenorphine may be an appropriate alternative for pain management over other opioids.
Learn More >Cognitive-affective factors influence the perception of pain and disability. These factors can lead to pain behaviors (PB) that can persist and become maladaptive. These maladaptive PB will further increase the risk of chronicity or persistence of symptoms and disability. Thus, clinicians must be prepared to recognize maladaptive PB in a clinical context. To date, in the context of assessment in a rehabilitation setting, PB in clinical settings are poorly documented. The main objective of this study was to identify direct observation methods and critically appraise them in order to propose recommendations for practice. As a secondary objective, we explored and extracted the different observable PB that patients could exhibit and that clinicians could observe.
Learn More >Fibromyalgia and small fibre neuropathy are two diseases leading to chronic widespread pain, and it is difficult to differentiate them in order to provide appropriate care. In this review, we will describe the pathophysiological and clinical differences between fibromyalgia and small fibre neuropathy. In fibromyalgia, pain is increased by dysregulation of central pain processing while small fibre neuropathy pain is related to loss or dysfunction of intraepidermal small nerve fibres. Higher pain intensity; stabbing pain and paraesthesia; allodynia; dry eyes/mouth; changed pattern or sweating on body; skin colour alterations/modifications; reduced hair/nail growth on lower extremities; warm or cold hypoesthesia could be more common in small fibre neuropathy whereas headache or temporo-mandibular disorder point toward fibromyalgia. Length-dependent distribution of pain is common in small fibre neuropathy but can also affect the whole body. Anxiety or depression are common in these two diseases, but post-traumatic stress disorder and physical or sexual abuse in childhood or adulthood suggest fibromyalgia. Inflammatory disease or musculoskeletal disease is frequently reported with fibromyalgia whereas metabolic disorders (especially diabetes mellitus), neurotoxic exposure, Sjogren's syndrome, sarcoidosis, HIV are the main diseases associated with small fibre neuropathy. Skin biopsy, quantitative sensory testing, laser evoked potentials, confocal corneal microscopy or electrochemical skin conductance can help to discriminate between fibromyalgia and small fibre neuropathy.
Learn More >Among postmenopausal women with estrogen receptor-positive breast cancer, more than 80% receive hormone therapy including aromatase inhibitors (AIs). Half of them develop chronic arthralgia – characterized by symmetric articular pain, carpal tunnel syndrome, morning stiffness, myalgia and a decrease in grip strength – which is associated with treatment discontinuation. Only a few animal studies have linked AI treatment to nociception, and none to arthralgia. Thus, we developed a new chronic AI-induced nociceptive disorder model mimicking clinical symptoms induced by AIs, using subcutaneous letrozole pellets in ovariectomized (OVX) rats. Following plasma letrozole dosage at the end of the experiment (day 73), only rats with at least 90 ng/mL of letrozole were considered significantly exposed to letrozole (OVX + high LTZ group), whereas treated animals with less than 90 ng/mL were pooled in the OVX + low LTZ group. Chronic nociceptive disorder set in rapidly and was maintained for more than 70 days in the OVX + high LTZ group. Furthermore, OVX + high LTZ rats saw no alteration in locomotion, myalgia or experimental anxiety during this period. Bone parameters of the femora were significantly altered in all OVX rats compared to Sham+vehicle pellet. A mechanistic analysis focused on TRPA1, receptor suspected to mediate AI-evoked pain, and showed no modification in its expression in the DRG. This new long-lasting chronic rat model, efficiently reproduces the symptoms of AI-induced nociceptive disorder affecting patients' daily activities and quality-of-life. It should help to study the pathophysiology of this disorder and to promote the development of new therapeutic strategies.
Learn More >Temporomandibular disorders (TMD) are a group of diseases in the oral and maxillofacial region that can manifest as acute or chronic persistent pain, affecting millions of people worldwide. Although hundreds of studies have explored mechanisms and treatments underlying TMD, multiple pathogenic factors and diverse clinical manifestations make it still poorly managed. Appropriate animal models are helpful to study the pathogenesis of TMD and explore effective treatment measures. At present, due to the high cost of obtaining large animals, rodents and rabbits are often used to prepare TMD animal models. Over the past decade, various animal models have been intensively developed to understand neurobiological and molecular mechanisms of TMD, and seek effective treatments. Although these models cannot carry out all clinical features, they are valuable in revealing the mechanisms of TMD and creating curative access. Currently, there are multitudinous animal models of TMD research. They can be constructed in different means and summarized into four ways according to the various causes and symptoms, including chemical induction (intra-articular injection of ovalbumin, collagenase, formalin, vascular endothelial growth factor, intramuscular injection of complete Freund's adjuvant, etc.), mechanical stress stimulation (passive mouth opening, change of chewing load), surgical operation (partial disc resection, joint disc perforation) and psychological stress induction. Here, we summarize and discuss different approaches of animal models for determining neurophysiological and mechanical mechanisms of TMD and assess their advantages and limitations, respectively.
Learn More >