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Migraine is the second leading cause of disability worldwide. Most patients with migraine discontinue medications due to inefficacy or adverse effects. Mindfulness-based stress reduction (MBSR) may provide benefit.
Learn More >To investigate the effect of therapeutic suggestions played to patients through earphones during surgery on postoperative pain and opioid use.
Learn More >Migraine with aura is a common but poorly understood sensory circuit disorder. Monogenic models allow an opportunity to investigate its mechanisms, including spreading depolarization (SD), the phenomenon underlying migraine aura. Using fluorescent glutamate imaging, we show that awake mice carrying a familial hemiplegic migraine type 2 (FHM2) mutation have slower clearance during sensory processing, as well as previously undescribed spontaneous "plumes" of glutamate. Glutamatergic plumes overlapped anatomically with a reduced density of GLT-1a-positive astrocyte processes and were mimicked in wild-type animals by inhibiting glutamate clearance. Plume pharmacology and plume-like neural Ca events were consistent with action-potential-independent spontaneous glutamate release, suggesting plumes are a consequence of inefficient clearance following synaptic release. Importantly, a rise in basal glutamate and plume frequency predicted the onset of SD in both FHM2 and wild-type mice, providing a novel mechanism in migraine with aura and, by extension, the other neurological disorders where SD occurs.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequently reported adverse effects of cancer treatment. CIPN often persists long after treatment completion and has detrimental effects on patient's quality of life. There are no efficacious FDA-approved drugs for CIPN. We recently demonstrated that nasal administration of mesenchymal stem cells (MSC) reverses the cognitive deficits induced by cisplatin in mice. Here we show that nasal administration of MSC after cisplatin- or paclitaxel treatment- completely reverses signs of established CIPN, including mechanical allodynia, spontaneous pain, and loss of intraepidermal nerve fibers (IENF) in the paw. The resolution of CIPN is associated with normalization of the cisplatin-induced decrease in mitochondrial bioenergetics in DRG neurons. Nasally administered MSC enter rapidly the meninges of the brain, spinal cord and peripheral lymph nodes to promote IL-10 production by macrophages. MSC mediated resolution of mechanical allodynia recovery of IENFs and restoration of DRG mitochondrial function critically depends on IL-10 production. MSC from IL-10 knockout animals are not capable of reversing the symptoms of CIPN. Moreover WT MSC do not reverse CIPN in mice lacking IL-10 receptors on peripheral sensory neurons. In conclusion only two nasal administrations of MSC fully reverse CIPN and the associated mitochondrial abnormalities via an IL-10 dependent pathway. Since MSC are already applied clinically we propose that nasal MSC treatment could become a powerful treatment for the large group of patients suffering from neurotoxicities of cancer treatment.
Learn More >There are clinically relevant sex differences in acute and chronic pain mechanisms, but we are only beginning to understand their mechanistic basis. Transcriptome analyses of rodent whole dorsal root ganglion (DRG) have revealed sex differences, mostly in immune cells. We examined the transcriptome and translatome of the mouse DRG with the goal of identifying sex differences.
Learn More >Binding of arrestin to phosphorylated G-protein-coupled receptors (GPCRs) controls many aspects of cell signaling. The number and arrangement of phosphates may vary substantially for a given GPCR, and different phosphorylation patterns trigger different arrestin-mediated effects. Here, we determine how GPCR phosphorylation influences arrestin behavior by using atomic-level simulations and site-directed spectroscopy to reveal the effects of phosphorylation patterns on arrestin binding and conformation. We find that patterns favoring binding differ from those favoring activation-associated conformational change. Both binding and conformation depend more on arrangement of phosphates than on their total number, with phosphorylation at different positions sometimes exerting opposite effects. Phosphorylation patterns selectively favor a wide variety of arrestin conformations, differently affecting arrestin sites implicated in scaffolding distinct signaling proteins. We also reveal molecular mechanisms of these phenomena. Our work reveals the structural basis for the long-standing "barcode" hypothesis and has important implications for design of functionally selective GPCR-targeted drugs.
Learn More >Although the widely used single L-enantiomers of local anesthetics have less toxic effects on the cardiovascular and central nervous systems, the mechanisms mediating their antinociceptive actions are not well understood. The authors hypothesized that significant differences in the ion channel blocking abilities of the enantiomers of bupivacaine would be identified.
Learn More >Small-fiber neuropathy (SFN), characterized by distal unmyelinated/thinly-myelinated fiber loss, produces a combination of sensory dysfunction and neuropathic pain. Gain-of-function variants in the sodium channel Nav1.7 that produce DRG neuron hyperexcitability are present in 5-10% of patients with idiopathic painful SFN. We created two independent knock-in mouse-lines carrying the Nav1.7-I228M gain-of-function variant, found in idiopathic SFN. Whole-cell patch-clamp and multi-electrode-array recordings show that Nav1.7-I228M knock-in DRG neurons are hyperexcitable compared to wild-type littermate-control neurons, but in spite of this, Nav1.7-I228M mice do not display mechanical or thermal-hyperalgesia or intraepidermal nerve-fiber loss in vivo. Therefore, while these two Nav1.7-I228M knock-in mouse lines recapitulate the DRG neuron hyperexcitability associated with gain-of function mutations in Nav1.7, they do not recapitulate the pain or neuropathy phenotypes seen in patients. We suggest that the relationship between hyper-excitability in sensory neurons and the pain experienced by these patients may be more complex than previously appreciated and highlights the challenges in modelling channelopathy pain disorders in mice.
Learn More >Migraine is one of the top 5 most prevalent childhood diseases; however, effective treatment strategies for pediatric migraine are limited. For example, standard adult pharmaceutical therapies are less effective in children and can carry undesirable side effects. To develop more effective treatments, improved knowledge of the biology underlying pediatric migraine is necessary. One theory is that migraine results from an imbalance in cortical excitability. Magnetic resonance spectroscopy (MRS) studies show changes in GABA and glutamate levels (the primary inhibitory and excitatory neurotransmitters in the brain, respectively) in multiple brain regions in adults with migraine; however, they have yet to be assessed in children with migraine. Using MRS and GABA-edited MRS, we show that children (7-13 years) with migraine and aura had significantly lower glutamate levels in the visual cortex compared to controls, the opposite to results seen in adults. In addition, we found significant correlations between metabolite levels and migraine characteristics; higher GABA levels were associated with higher migraine burden. We also found that higher glutamate in the thalamus and higher GABA/Glx ratios in the sensorimotor cortex were associated with duration since diagnosis, i.e., having migraines longer. Lower GABA levels in the sensorimotor cortex were associated with being closer to their next migraine attack. Together, this indicates that GABA and glutamate disturbances occur early in migraine pathophysiology and emphasizes that evidence from adults with migraine cannot be immediately translated to pediatric sufferers. This highlights the need for further mechanistic studies of migraine in children, to aid in development of more effective treatments.
Learn More >There is a long-held belief that physical activities such as lifting with a flexed spine is generally harmful for the back and can cause low back pain (LBP), potentially reinforcing fear avoidance beliefs underlying pain-related fear. In chronic LBP patients, pain-related fear has been shown to be associated with reduced lumbar range of motion during lifting, suggesting a protective response to pain. However, despite short term beneficial effects for tissue health, recent evidence suggests that maintaining a protective trunk movement strategy may also pose a risk for (persistent) LBP due to possible pro-nociceptive consequences of altered spinal motion, potentially leading to increased loading on lumbar tissues. Yet, it is unknown if similar protective movement strategies already exist in pain-free individuals which would yield potential insights into the role of fear avoidance beliefs in motor behavior in the absence of pain. Therefore, the aim of this study is to test whether fear avoidance beliefs influence spinal motion during lifting in a healthy cohort of pain-free adults without a history of chronic pain. The study subjects (N=57) filled out several pain-related fear questionnaires and were asked to perform a lifting task (5kg-box). High-resolution spinal kinematics were assessed using an optical motion capturing system. Time-sensitive analyses were performed based on statistical parametric mapping. The results demonstrated time-specific and negative relationships between self-report measures of pain-related fear and lumbar spine flexion angles during lifting, indicating potential unfavorable interactions between psychological factors and spinal motion during lifting in pain-free subjects.
Learn More >Early life stress is known to affect the development of the nervous system and its function at a later age. It increases the risk to develop psychiatric disorders as well as chronic pain and its associated affective comorbidities across the lifespan. GABAergic inhibition is important for the regulation of central function and related behaviors, including nociception, anxiety or social interactions, and requires low intracellular chloride levels. Of particular interest, the oxytocinergic (OTergic) system exerts potent anxiolytic, analgesic and pro-social properties and is known to be involved in the regulation of chloride homeostasis and to be impaired following early life stress.
Learn More >Acupuncture is a complex multi-component treatment that has shown promise for the treatment of Fibromyalgia (FM), however, clinical trials have shown mixed results, possibly due to heterogeneous methodology and lack of understanding of the underlying mechanism of action. We sought to understand the specific contribution of somatosensory afference to improvements in clinical pain, and the specific brain circuits involved.
Learn More >The pervasive use of opioid compounds for pain relief is rooted in their utility as one of the most effective therapeutic strategies for providing analgesia. While the detrimental side effects of these compounds have significantly contributed to the current opioid epidemic, opioids still provide millions of patients with reprieve from the relentless and agonizing experience of pain. The human experience of pain has long recognized the perceived unpleasantness entangled with a unique sensation that is immediate and identifiable from the first-person subjective vantage point as "painful." From this phenomenological perspective, how is it that opioids interfere with pain perception? Evidence from human lesion, neuroimaging, and preclinical functional neuroanatomy approaches is sculpting the view that opioids predominately alleviate the affective or inferential appraisal of nociceptive neural information. Thus, opioids weaken pain-associated unpleasantness rather than modulate perceived sensory qualities. Here, we discuss the historical theories of pain to demonstrate how modern neuroscience is revisiting these ideas to deconstruct the brain mechanisms driving the emergence of aversive pain perceptions. We further detail how targeting opioidergic signaling within affective or emotional brain circuits remains a strong avenue for developing targeted pharmacological and gene-therapy analgesic treatments that might reduce the dependence on current clinical opioid options.
Learn More >Deep brain stimulation (DBS) of the subthalamic nucleus, pallidum, and thalamus is an established therapy for various movement disorders. Limbic targets have also been increasingly explored for their application to neuropsychiatric and cognitive disorders. The brainstem constitutes another DBS substrate, although the existing literature on the indications for and the effects of brainstem stimulation remains comparatively sparse. The objective of this review was to provide a comprehensive overview of the pertinent anatomy, indications, and reported stimulation-induced acute and long-term effects of existing white and grey matter brainstem DBS targets. We systematically searched the published literature, reviewing clinical trial articles pertaining to DBS brainstem targets. Overall, 164 studies describing brainstem DBS were identified. These studies encompassed 10 discrete structures: periaqueductal/periventricular grey (n = 63), pedunculopontine nucleus (n = 48), ventral tegmental area (n = 22), substantia nigra (n = 9), mesencephalic reticular formation (n = 7), medial forebrain bundle (n = 8), superior cerebellar peduncles (n = 3), red nucleus (n = 3), parabrachial complex (n = 2), and locus coeruleus (n = 1). Indications for brainstem DBS varied widely and included central neuropathic pain, axial symptoms of movement disorders, headache, depression, and vegetative state. The most promising results for brainstem DBS have come from targeting the pedunculopontine nucleus for relief of axial motor deficits, periaqueductal/periventricular grey for the management of central neuropathic pain, and ventral tegmental area for treatment of cluster headaches. Brainstem DBS has also acutely elicited numerous motor, limbic, and autonomic effects. Further work involving larger, controlled trials is necessary to better establish the therapeutic potential of DBS in this complex area.
Learn More >Neurosurgical treatments for trigeminal neuralgia (TN) can provide long-lasting pain relief, however, some patients fail to respond and undergo multiple, repeat procedures. Surgical outcomes can vary depending on the type of TN, but the reasons for this are not well understood. Neuroimaging studies of TN point to abnormalities in the brainstem trigeminal fibers, however, whether this is a common characteristic of treatment non-response across different subtypes of TN is unknown. Here, we used diffusion tensor imaging (DTI) to determine whether the brainstem trigeminal fiber microstructure is a common biomarker of surgical response in TN and whether the extent of these abnormalities is associated with the likelihood of response across subtypes of TN. We studied 98 patients with TN (61 classical TN, 26 TN secondary to multiple sclerosis, and 11 TN associated with a solitary pontine lesion) who underwent neurosurgical treatment and 50 healthy controls. We assessed treatment response using pain intensity measures and examined microstructural features by extracting pre-treatment DTI metrics from the proximal pontine segment of the trigeminal nerves. We found that microstructural abnormalities in the affected pontine trigeminal fibers (notably, lower fractional anisotropy and higher radial diffusivity) highlight treatment non-responders (n=47) compared to responders (n=51) and controls, and that the degree of abnormalities is associated with the likelihood of surgical response across subtypes of TN. These novel findings demonstrate the value of DTI as an objective, non-invasive tool for the prediction of treatment response and elucidate the features that distinguish treatment responders from non-responders in the TN population.
Learn More >Low back pain (LBP) is a leading cause of disability. However, the processes contributing to disability are not well understood. Therefore, this study 1) empirically derived LBP subgroups and 2) validated these subgroups using walking performance, pain, and disability measures. Seventy adults with LBP underwent testing for a priori determined sensory (temporal summation; conditioned pain modulation), psychological (positive coping; negative coping), and motor (trunk extensor muscle activation during forward bending and walking) measures. A hierarchical cluster analysis determined subgroups that were then validated using walking (walking speed; Timed Up and Go (TUG); Timed Up and Go-Cognitive (TUG-Cog); obstacle negotiation) and clinical (Brief Pain Inventory; Oswestry Disability Index; low back pressure pain threshold) measures. Two subgroups were derived: 1) a "Maladaptive" subgroup (n=21) characterized by low positive coping, high negative coping, low pain modulation, and atypical trunk extensor activation; and 2) an "Adaptive" subgroup (n=49) characterized by high positive coping, low negative coping, high pain modulation, and typical trunk extensor activation. There were subgroup differences on 7 out of 12 validation measures. The Maladaptive subgroup had reduced walking performance (slower self-selected walking speed, TUG completion, and obstacle approach and crossing speed) and worse clinical presentation (higher pain intensity, pain interference, and disability) (moderate to large effect sizes; p's<0.05). Findings support the construct validity of this multidimensional subgrouping approach. Longitudinal studies are needed to determine if the Maladaptive subgroup is predictive of poor outcomes, such as pain chronicity or persistent disability.
Learn More >Empathy for pain allows one to recognize, understand, and respond to another person's pain in a prosocial manner. Young children develop empathy for pain later than empathy for other negative emotions (e.g., sadness), which may be due to social learning. How parents reminisce with children about past painful events has been linked to children's pain cognitions (e.g., memory) and broader socioemotional development. The present study examined how parent-child reminiscing about pain may be linked to children's empathic behaviors toward another person's pain.
Learn More >C-tactile (CT) afferents were long-believed to be lacking in humans, but were subsequently shown to densely innervate the face and arm skin, and to a lesser extent the leg. Their firing frequency to stroking touch at different velocities has been correlated with ratings of tactile pleasantness. CT afferents were thought to be absent in human glabrous skin; however, tactile pleasantness can be perceived across the whole body, including glabrous hand skin. We used microneurography to investigate mechanoreceptive afferents in the glabrous skin of the human hand, during median and radial nerve recordings. We describe CTs found in the glabrous skin, with comparable characteristics to those in hairy arm skin, and detail recordings from three such afferents. CTs were infrequently encountered in the glabrous skin and we estimate that the ratio of recorded CTs relative to myelinated mechanoreceptors (1:80) corresponds to an absolute innervation density of around 7 times lower than in hairy skin. This sparse innervation sheds light on discrepancies between psychophysical findings of touch perception on glabrous skin and hairy skin, although the role of these CT afferents in the glabrous skin remains subject to future work.
Learn More >To investigate if calcitonin gene-related peptide infusion induces migraine-like attacks in chronic migraine patients.
Learn More >Being born preterm is related to adverse health effects later in life. We studied whether preterm birth predicts the risk of migraine.
Learn More >Pain is one of the first presenting symptoms in patients with head and neck cancer, who often develop chronic and debilitating pain as the disease progresses. Pain is also an important prognostic marker for survival. Unfortunately, patients rarely receive effective pain treatment due to our limited knowledge of the mechanisms underlying head and neck cancer pain (HNCP). Pain is often associated with neuroinflammation and particularly interleukin (IL)-1 signaling. The purpose of this study is to develop a novel syngeneic model of HNCP in immunocompetent mice to examine the contribution of IL-1 signaling.
Learn More >Chronic low back pain (cLBP) has been associated with changes in brain plasticity. Non-pharmacological therapies such as Manual Therapy (MT) have shown promise for relieving cLBP. However, translational neuroimaging research is needed to understand potential central mechanisms supporting MT. We investigated the effect of MT on resting-state salience network (SLN) connectivity, and whether this was associated with changes in clinical pain. Fifteen cLBP patients, and 16 matched healthy controls (HC) were scanned with resting functional Magnetic Resonance Imaging (fMRI), before and immediately after a MT intervention (cross-over design with two separate visits, pseudorandomized, grades V 'Manipulation' and III 'Mobilization' of the Maitland Joint Mobilization Grading Scale). Patients rated clinical pain (0-100) pre- and post-therapy. SLN connectivity was assessed using dual regression probabilistic independent component analysis. Both manipulation (Pre: 39.43 ± 16.5, Post: 28.43 ± 16.5) and mobilization (Pre: 38.83 ± 17.7, Post: 31.76 ± 19.4) reduced clinical back pain (p<0.05). Manipulation (but not mobilization) significantly increased SLN connectivity to thalamus and primary motor cortex. Additionally, a voxelwise regression indicated that greater MT-induced increase in SLN connectivity to the lateral prefrontal cortex was associated with greater clinical back pain reduction immediately after intervention, for both manipulation (R=-0.8) and mobilization (R=-0.54). Our results suggest that MT is successful in reducing clinical low back pain by both spinal manipulation and spinal mobilization. Furthermore, this reduction post-manipulation occurs via modulation of SLN connectivity to sensorimotor, affective, and cognitive processing regions. Perspective: Manual Therapy both reduces clinical low back pain and modulates brain activity important for the processing of pain. This modulation was shown by increased functional brain connectivity between the salience network and brain regions involved in cognitive, affective, and sensorimotor processing of pain.
Learn More >Chronic pain prevention and treatment constitute a challenge for occupational health. The aim of this study was to provide data on workers in a variety of jobs and multiple contexts to determine the prevalence and characteristics of different chronic pain disorders, in view to highlighting possible new targets for preventive actions. 1,008 participants working in 14 French IKEA stores were analyzed in this observational study on the basis of their responses to surveys on their sociodemographic characteristics, psychosocial factors, lifestyle and pain disorders. The prevalences of chronic pain, moderate-to-severe chronic pain and high-impact chronic pain were 49%, 30% and 11%, respectively. Chronic pain was predominantly located in the neck and back, and identified mostly as nociceptive, with, for some participants, a neuropathic component (mixed pain). The majority of chronic pain was reported as being due to professional activity, and causing at least one work stoppage during the past year in half of the participants. Jobs that were the most common sources of chronic pain were those with a higher proportion of repetitive gestures, no consecutive days of rest, stress at work, such as cash-register/catering jobs. Overall, this study highlighted profiles at risk of developing or suffering from chronic pain, and several associated factors: ≥40 years old, female sex, overweight/obesity, repetitive gestures, no consecutive days of rest, stress, catastrophism, workplace environment, poor quality of life and mental state. In conclusion, these data give interesting information on the characteristics of workers with chronic pain and highlight profiles of participants. REGISTRATION NUMBER: NCT03931694 PERSPECTIVE: This study provides important information about the features of chronic pain in a model of a working population of Western countries. This information can be used to propose preventive actions.
Learn More >In this randomized, double-blind, placebo-controlled trial, we evaluated the role of transcutaneous electrical nerve stimulation (TENS) in the multimodal treatment (non-opioid analgesics and kinesiotherapy) of postoperative pain following open inguinal hernia repair. In total, 80 males participants with elective primary unilateral hernia Lichtenstein repair were randomly allocated to receive TENS or a placebo-TENS procedure. The TENS group received local and segmental conventional TENS on the first and second postoperative days. In the placebo-TENS group, intensity was set at 0-0.5mA. Change of pain level at rest, when walking, when standing up from bed, pressure algometry parameters and additional analgesic use were the main outcomes. Reduction of VAS pain score and absolute and relative pain relief were observed in the TENS group following the procedures compared to the placebo-TENS group (p<0.001). The pressure pain threshold and maximal tolerable pressure in the hernia side were equal before the TENS procedure in both groups (p=0.84), but after the procedure, these were higher in TENS group (p<0.001). Additional non-opioid analgesics requirements were lower in the TENS group on the first and second postoperative days (p<0.001). TENS is a safe procedure that can reduce postoperative pain and analgesic use after open inguinal hernia repair. The study was registered in the database of clinicaltrials.gov (register number NCT03739060) Perspective This article presents TENS as a safe and effective non-pharmacologic intervention to reduce post-operative pain after open inguinal hernia repair. TENS could be used in daily practice as part of a multimodal postoperative pain treatment, especially for patients suffering from hyperalgesia.
Learn More >The worldwide diabetes epidemic is estimated to currently afflict almost 500 million persons. Long-term diabetes damages multiple organ systems with the blood vessels, eyes, kidneys and nervous systems being particularly vulnerable. These complications of diabetes reduce lifespan, impede quality of life and impose a huge social and economic burden on both the individual and society. Peripheral neuropathy is a debilitating complication that will impact over half of all persons with diabetes. There is no treatment for diabetic neuropathy and a disturbingly long history of therapeutic approaches showing promise in preclinical studies but failing to translate to the clinic. These failures have prompted re-examination of both the animal models and clinical trial design. This review focuses on the functional and structural parameters used as indices of peripheral neuropathy in preclinical and clinical studies and the extent to which they share a common pathogenesis and presentation. Nerve conduction studies in large myelinated fibers have long been the mainstay of preclinical efficacy screening programs and clinical trials, supplemented by quantitative sensory tests. However, a more refined approach is emerging that incorporates measures of small fiber density in the skin and cornea alongside these traditional assays at both preclinical and clinical phases.
Learn More >Chronic nonspecific low back pain (LBP) is very common; it is defined as pain without a recognizable etiology that lasts for more than three months. Some clinical practice guidelines suggest that acupuncture can offer an effective alternative therapy. This review is a split from an earlier Cochrane review and it focuses on chronic LBP.
Learn More >Complex regional pain syndrome (CRPS) is a debilitating neuroinflammatory condition of unknown etiology. Symptoms include excruciating pain and trophic changes in the limbs as defined by the Budapest criteria. The severity and functional recovery of CRPS, unlike most pain conditions, is quantifiable using a variation of the Budapest criteria known as the CRPS severity score. Like many chronic pain conditions, CRPS is difficult to treat once pain has been present for more than 12 months. However, previous work has demonstrated that a subset of patients with new-onset CRPS (~50%) improve if treated within one year, while the rest have minimal to no symptom improvement. Unfortunately, this leads to permanent disability and often requires invasive and costly treatments such as spinal cord stimulation or long-term opioid therapy. Because the etiology is unknown, treatment is multimodal, and often supportive. Biomarkers that predict severity or resolution of symptoms would significantly change treatment but have not yet been identified. Interestingly, there are case reports of remission or resolution of CRPS symptoms with the use of antibiotics known to affect the gut flora. Mouse studies have demonstrated that modulation of the gut microbiome is anti-nociceptive in visceral, inflammatory and neuropathic pain models. We hypothesize that the variable clinical potential for recovery and response to therapy in CRPS may be secondary to or reflected in changes in the gut microbiota. We suggest that the microbiota may mediate or reflect clinical status via the metabolome, activation of the immune system and/or microglial activation. We hypothesize that the gut microbiome is a potential mediator in development and persistence of CRPS symptoms and propose that the clinical condition of CRPS could provide a unique opportunity to identify biomarkers of the microbiota and potential therapies to prevent pain chronification.
Learn More >Emerging data points towards a possible aetiological and therapeutic relevance of trigeminal neurovascular contact in short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and perhaps in short lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). We aimed to assess the prevalence and significance of trigeminal neurovascular contact in a large cohort of consecutive SUNCT and SUNA patients and evaluate the radiological differences between them. The standard imaging protocol included high spatial and nerve-cistern contrast resolution imaging acquisitions of the cisternal segments of the trigeminal nerves and vessels. MRI studies were evaluated blindly by two expert evaluators and graded according to the presence, location and degree of neurovascular contact. The degree of contact was graded as with or without morphological changes. Neurovascular contact with morphological changes was defined as contact with distortion and/or atrophy. A total of 159 patients (SUNCT = 80; SUNA = 79) were included. A total of 165 symptomatic and 153 asymptomatic trigeminal nerves were analysed. The proportion of neurovascular contact on the symptomatic trigeminal nerves was higher (80.0%) compared to the asymptomatic trigeminal nerves (56.9%). The odds on having neurovascular contact over the symptomatic nerves was significantly higher than on the asymptomatic nerves [odds ratio (OR): 3.03, 95% confidence interval (CI) 1.84-4.99; P < 0.0001]. Neurovascular contact with morphological changes were considerably more prevalent on the symptomatic side (61.4%), compared to the asymptomatic side (31.0%) (OR 4.16, 95% CI 2.46-7.05; P < 0.0001). On symptomatic nerves, neurovascular contact with morphological changes was caused by an artery in 95.0% (n = 77/81). Moreover, the site of contact and the point of contact around the trigeminal root were respectively proximal in 82.7% (67/81) and superior in 59.3% (48/81). No significant radiological differences emerged between SUNCT and SUNA. The multivariate analysis of radiological predictors associated with the symptomatic side, indicated that the presence of neurovascular contact with morphological changes was strongly associated with the side of the pain (OR: 2.80, 95% CI 1.44-5.44; P = 0.002) even when adjusted for diagnoses. Our findings suggest that neurovascular contact with morphological changes is involved in the aetiology of SUNCT and SUNA. Along with a similar clinical phenotype, SUNCT and SUNA also display a similar structural neuroimaging profile, providing further support for the concept that the separation between them should be abandoned. Furthermore, these findings suggest that vascular compression of the trigeminal sensory root, may be a common aetiological factor between SUNCT, SUNA and trigeminal neuralgia thereby further expanding the overlap between these disorders.
Learn More >The human motor system has the capacity to act as an internal form of analgesia. Since the discovery of the potential influence of motor systems on analgesia in rodent models, clinical applications of targeting the motor system for analgesia have been implemented. However, a neurobiological basis for motor activation's effects on analgesia is not well defined. Motor-related analgesia (MRA) is a phenomenon wherein a decrease in pain symptoms can be achieved through either indirect or direct activation of the motor axis. To date, research has focused on (a) evaluating the pain-motor interaction as one focused on the acute protection from painful stimuli; (b) motor cortex stimulation for chronic pain; or (c) exercise as a method of improving chronic pain in animal and human models. This review evaluates (1) current knowledge surrounding how pain interferes with canonical neurological performance throughout the motor axis; and (2) the physiological basis for motor-related analgesia as a means to reduce pain symptom loads for patients. A proposal for future research directions is provided.
Learn More >A serious adverse effect of prescription opioid analgesics is addiction, both to these analgesics and to illicit drugs like heroin that also activate the µ-opioid receptor (MOR). Opioid use disorder (OUD) and opioid overdose deaths represent a current American health crisis, and the prescription of opioid analgesics has contributed significantly to this crisis. While prescription opioids are highly effective analgesics, there currently exists no facile way to use them for extended periods without the risk of addiction. If addiction caused by MOR-targeting analgesics could be blocked by blending in a new "antiaddiction" ingredient that does not diminish analgesia and does not introduce its own therapeutically limiting side effects, then continued clinical use of prescription opioids for treating pain could be maintained (or even enhanced) instead of curtailed. In this narrative review, we contextualize this hypothesis, first with a brief overview of the current American opioid addiction crisis. The neurobiology of 2 key receptors in OUD development, MOR and the κ-opioid receptor (KOR), is then discussed to highlight the neuroanatomical features and circuitry in which signal transduction from these receptors lie in opposition-creating opportunities for pharmacological intervention in curtailing the addictive potential of MOR agonism. Prior findings with mixed MOR/KOR agonists are considered before exploring new potential avenues such as biased KOR agonists. New preclinical data are highlighted, demonstrating that the G protein-biased KOR agonist nalfurafine reduces the rewarding properties of MOR-targeting analgesics and enhances MOR-targeting analgesic-induced antinociception. Finally, we discuss the recent discovery that a regulator of G protein signaling (namely, RGS12) is a key component of signaling bias at KOR, presenting another drug discovery target toward identifying a single agent or adjuvant to be added to traditional opioid analgesics that could reduce or eliminate the addictive potential of the latter drug.
Learn More >Chronic widespread musculoskeletal pain (CWP) is a characteristic symptom of fibromyalgia, which has been shown to be associated with an altered gut microbiome. Microbiome studies to date have not examined the milder CWP phenotype specifically nor have they explored the role of raised BMI. The aim of this study was to investigate whether the microbiome is abnormal in CWP.
Learn More >Chronic pelvic pain persists in some women with endometriosis even after lesion removal and optimized hormonal treatment.
Learn More >Dependence-like behaviour may complicate withdrawal and increase risk of relapse of medication overuse headache (MOH). The most effective treatment for reducing dependence-like behaviour is unknown.
Learn More >The aim of this study was to determine if the non-convulsant delta-opioid receptor (DOR) agonist, KNT-127, could inhibit migraine-associated endpoints.
Learn More >We sought to assess factors associated with the frequency of self-reported prescription opioid use in persons with migraine, including demographic variables, comorbidities, headache characteristics, and patterns of consultation.
Learn More >The past two decades has seen an influx of noninvasive neuromodulation devices aimed at treatment of various primary headache disorders, including cluster headache and migraine. This narrative review is to summarize the current options in noninvasive neuromodulation in migraine.
Learn More >Even though current prescribing trends reveal that high-dose opioid prescribing and opioid prescribing in general has decreased, sustained efforts are needed to help providers adopt and maintain safe prescribing behaviors. The purpose of this four-year type 2 effectiveness-implementation hybrid stepped wedge cluster randomized trial is to: (1) compare the clinical and cost effectiveness of electronic medical record-based clinical decision support [EMR-CDS] versus additional integrated, collaborative behavioral health [EMR-CDS + BHI-CCM] for opioid management of patients with co-morbid chronic non-cancer pain with depression or anxiety; and (2) examine facilitators and barriers to implementing these interventions within 35 primary care clinics in a integrated delivery health system. The EMR-CDS alerts providers to employ opioid risk mitigation and safe prescribing practices at the point of care. The BHI-CCM consists of primary care embedded community health workers for case management; licensed clinical social workers for cognitive behavioral therapy, and a clinical pharmacist for medication management who provide care management via telemedicine (virtual video or audio only visits) under the guidance of a consulting psychiatrist. The primary outcome is reduction in the percentage of patients with average daily opioid dose ≥50 mg morphine equivalent. Secondary outcomes include changes in service utilization, patient reported outcomes and processes of care. The investigators anticipate that study results will elucidate the role of technology versus care team optimization in changing opioid prescribing behaviors. The investigators further anticipate that integrated mental/behavioral health care will increase value-based care and the efficiency with which guideline concordant care is delivered.
Learn More >To identify factors associated with work productivity in adults with migraine, and accommodations or interventions to improve productivity or the workplace environment for them.
Learn More >Brief psychological interventions (BPIs) have demonstrated effectiveness in reducing substance use and related harm. No systematic review has examined their potential to reduce or prevent prescription opioid use or related harm, and/or pain intensity in opioid-using patients with chronic non-cancer pain (CNCP). Recognizing the importance of patient preferences in evidence-based practice, we also sought to assess patient interest in BPIs.
Learn More >In this study of 154 community-dwelling older adults with chronic non-cancer pain, we sought to assess participants' beliefs about pain as well as pain management treatments and determined the influence of those beliefs on participants' willingness to undertake three physician-recommended pain treatments, i.e., a pharmacologic, physical, and psychological therapy.
Learn More >To investigate learning processes underlying nocebo effects on itch, this study measured the efficacy of classical conditioning and observational learning for inducing nocebo effects on cowhage-evoked itch and scratching behaviour. A total of 58 healthy female participants were assigned to classical conditioning, observational learning, or sham conditioning groups. In the classical conditioning group, experimenters associated the application of an inert gel with increased itch intensity first-hand. In the observational learning group, a video of the conditioning paradigm was shown. Nocebo effects were measured as the difference in itch or scratching between control and nocebo test phase trials, compared between learning and control groups. Compared with sham conditioning, classical conditioning induced a significant nocebo effect on itch, while observational learning did not. No nocebo effect on scratching was detected. These results highlight the role that learning through direct experiences plays in pruritic symptoms. Future research should investigate how a patient's history of unsuccessful treatments shapes treatment outcomes.
Learn More >There has been a long-standing debate regarding the role of peripheral afferents in mediating rapid-onset anorexia among other responses elicited by peripheral inflammatory insults. Thus, the current study assessed the sufficiency of peripheral afferents expressing toll-like receptor 4 (TLR4) to the initiation of the anorexia caused by peripheral bacterial lipopolysaccharide (LPS). We generated a Tlr4 null (Tlr4) mouse in which Tlr4 expression is globally disrupted by a loxP-flanked transcription blocking cassette. This novel mouse model allowed us to restore the endogenous TLR4 expression in specific cell types. Using Zp3-Cre and Na1.8-Cre mice, we produced mice that express TLR4 in all cells (Tlr4 X Zp3-Cre) and in peripheral afferents (Tlr4 X Na1.8-Cre), respectively. We validated the Tlr4 mice, which were phenotypically identical to previously reported global TLR4 knock-out mice. Contrary to our expectations, the administration of LPS did not cause rapid-onset anorexia in mice with Na1.8-restricted TLR4. The later result prompted us to identify Tlr4-expressing vagal afferents using hybridization. , we found that Tlr4 mRNA was primarily enriched in vagal Na1.8 afferents located in the jugular ganglion that co-expressed Calcitonin gene-related peptide (CGRP). , the application of LPS to cultured Na1.8-restricted TLR4 afferents was sufficient to stimulate the release and expression of CGRP. In summary, we demonstrated using a new mouse model that vagally-expressed TLR4 is selectively involved in stimulating the release of CGRP, but not in causing anorexia. Using a new transgenic mouse model, our data establish that TLR4 is both sufficient and required for the release of CGRP from a subset of vagal afferents. This finding may be relevant to the understanding of how bacterial infections modulate nerves.
Learn More >Engineered human mini-brains, made possible by knowledge from the convergence of precision microengineering and cell biology, permit systematic studies of complex neurological processes and of pathogenesis beyond what can be done with animal models. By culturing human brain cells with physiological microenvironmental cues, human mini-brain models reconstitute the arrangement of structural tissues and some of the complex biological functions of the human brain. In this Review, we highlight the most significant developments that have led to microphysiological human mini-brain models. We introduce the history of mini-brain development, review methods for creating mini-brain models in static conditions, and discuss relevant state-of-the-art dynamic cell-culture systems. We also review human mini-brain models that reconstruct aspects of major neurological disorders under static or dynamic conditions. Engineered human mini-brains will contribute to advancing the study of the physiology and aetiology of neurological disorders, and to the development of personalized medicines for them.
Learn More >Opioid abuse has devastating effects on patients, their families, and society. Withdrawal symptoms are severely unpleasant, prolonged, and frequently hinder recovery or lead to relapse. The sharp increase in abuse and overdoses arising from the illicit use of potent and rapidly-acting synthetic opioids, such as fentanyl, highlights the urgency of understanding the withdrawal mechanisms related to these drugs. Progress is impeded by inconsistent reports on opioid withdrawal in different preclinical models. Here, using rats and mice of both sexes, we quantified withdrawal behaviors during spontaneous and naloxone-precipitated withdrawal, following two weeks of intermittent fentanyl exposure. We found that both mice and rats lost weight during exposure and showed increased signs of distress during spontaneous and naloxone precipitated withdrawal. However, these species differed in their expression of withdrawal associated pain, a key contributor to relapse in humans. Spontaneous or ongoing pain was preferentially expressed in rats in both withdrawal conditions, while no change was observed in mice. In contrast, withdrawal associated thermal hyperalgesia was found only in mice. These data suggest that rats and mice diverge in how they experience withdrawal and which aspects of the human condition they most accurately model. These differences highlight each species' strengths as model systems and can inform experimental design in studies of opioid withdrawal.
Learn More >The risk constructs based on psychological risk factors (e.g. pain catastrophizing, PC) and sensitization risk factors (e.g. pressure pain threshold, PPT) are important in research and clinical practice. While most research looks at individual constructs, but doesn't consider how different constructs might interact within the same individual. A cumulative impact evaluation of psychological and sensitization risk factors on pain-related outcomes may help guide us in the risk assessment of patients with pain conditions. The aim of this study is to evaluate the cumulative impact of these psychological PC and sensitization PPT risk factors on pain-related outcomes (activity avoidance, pain severity and disability) considering covariates.
Learn More >The voltage-gated sodium channel Na1.8 mediates the tetrodotoxin-resistant (TTX-R) Na current in nociceptive primary sensory neurons, which has an important role in the transmission of painful stimuli. Here, we describe the functional modulation of the human Na1.8 α-subunit in oocytes by auxiliary β subunits. We found that the β3 subunit down-regulated the maximal Na current amplitude and decelerated recovery from inactivation of hNa1.8, whereas the β1 and β2 subunits had no such effects. The specific regulation of Na1.8 by the β3 subunit constitutes a potential novel regulatory mechanism of the TTX-R Na current in primary sensory neurons with potential implications in chronic pain states. In particular, neuropathic pain states are characterised by a down-regulation of Na1.8 accompanied by increased expression of the β3 subunit. Our results suggest that these two phenomena may be correlated, and that increased levels of the β3 subunit may directly contribute to the down-regulation of Na1.8. To determine which domain of the β3 subunit is responsible for the specific regulation of hNa1.8, we created chimeras of the β1 and β3 subunits and co-expressed them with the hNa1.8 α-subunit in oocytes. The intracellular domain of the β3 subunit was shown to be responsible for the down-regulation of maximal Na1.8 current amplitudes. In contrast, the extracellular domain mediated the effect of the β3 subunit on hNa1.8 recovery kinetics.
Learn More >Little is known about the effects of spinal cord stimulation (SCS) on chronic low back pain (CLBP) patients with no history of previous spine surgery. Using our prospectively collected database, we evaluate improvements in patients with and without previous spine surgery one-year post SCS implantation.
Learn More >The main function of pain is to automatically draw attention towards sources of potential injury. However, pain sometimes needs to be inhibited in order to address or pursue more relevant tasks. Elucidating the factors that influence how people manage this relationship between pain and task performance is essential to understanding the disruptive nature of pain and its variability between individuals. Here, 41 healthy adults completed a challenging working memory task (2-back task) while receiving painful thermal stimulations. Examining the trial-by-trial relationship between pain perception and task performance revealed that pain's disruptive effects on performance were mediated by self-reported pain intensity, and that the analgesic effects of a competing task were influenced by task performance. We found that higher pain catastrophizing, higher trait anxiety, and lower trait mindfulness were associated with larger trade-offs between pain perception and task performance, suggesting that these psychological factors can predict increased fluctuations between disruption by pain and analgesia from a competing task. Altogether these findings provide an important and novel perspective on our understanding of individual differences in the interplay between pain and ongoing task performance.
Learn More >The embryonic rat dorsal root ganglion (DRG) neuron-derived 50B11 cell line is a promising sensory neuron model expressing markers characteristic of NGF and GDNF-dependent C-fibre nociceptors. Whether these cells have the capacity to develop into distinct nociceptive subtypes based on NGF- or GDNF-dependence has not been investigated. Here we show that by augmenting forskolin (FSK) and growth factor supplementation with NGF or GDNF, 50B11 cultures can be driven to acquire differential functional responses to common nociceptive agonists capsaicin and ATP respectively. In addition, to previous studies, we also demonstrate that a differentiated neuronal phenotype can be maintained for up to 7 days. Western blot analysis of nociceptive marker proteins further demonstrates that the 50B11 cells partially recapitulate the functional phenotypes of classical NGF-dependent (peptidergic) and GDNF-dependent (non-peptidergic) neuronal subtypes described in DRGs. Further, 50B11 cells differentiated with NGF/FSK, but not GDNF/FSK, show sensitization to acute prostaglandin E2 treatment. Finally, RNA-Seq analysis confirms that differentiation with NGF/FSK or GDNF/FSK produces two 50B11 cell subtypes with distinct transcriptome expression profiles. Gene ontology comparison of the two subtypes of differentiated 50B11 cells to rodent DRG neurons studies shows significant overlap in matching or partially matching categories. This transcriptomic analysis will aid future suitability assessment of the 50B11 cells as a high-throughput nociceptor model for a broad range of experimental applications. In conclusion, this study shows that the 50B11 cell line is capable of partially recapitulating features of two distinct types of embryonic NGF and GDNF-dependent nociceptor-like cells.
Learn More >Phonophobia in migraineurs may be due to lower hearing threshold (HT) and higher brainstem neuronal excitability. We report correlation of phonophobia in migraineurs with HT, brain stem auditory evoked potential (BAEP) findings and auditory triggers. Sixty-one migraineurs and 101 controls were included for HT, of whom 59 migraineurs and 31 controls had BAEP studies. Clinical details, migraine triggers and headache frequency were noted. Hearing threshold was measured, and amplitudes of waves I to V of BAEP studies were measured. Migraineurs had lower HT compared with controls (41.61 ± 5.25 vs. 45.39 ± 6.26 dB; p < 0.001) especially in chronic migraine (40.24 ± 4.81; P < 0.001). Hearing threshold correlated with headache frequency (P < 0.05) and auditory, visual and tactile (P < 0.05) triggers. Hearing threshold was lower during headache (P < 0.001). Wave II, III and IV amplitudes of BAEP were higher in migraineurs than the controls. Wave II (P < 0.05) and III (P < 0.05) amplitudes correlated with HT. Migraineurs have lower HT, especially in those having chronic migraine, ictal HT recording and multiple sensory triggers. Higher amplitudes of BAEP waves in migraineurs and its relationship with frequency of headache and HT suggest sensitization of brainstem auditory neurons.
Learn More >Nerve injury-induced changes in gene expression in the dorsal root ganglion (DRG) contribute to neuropathic pain genesis. Eukaryotic initiation factor 4 gamma 2 (eIF4G2) is a general repressor of cap-dependent mRNA translation. Whether DRG eIF4G2 participates in nerve injury-induced alternations in gene expression and nociceptive hypersensitivity is unknown.
Learn More >Translation regulation in the context of aged-associated inflammation and behavioral impairments is not well characterized. Aged individuals experience lower life quality due to behavioral impairments. In this study, we used young and aged transgenic mice that are unable to activate the cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E) to examine the role of protein translation control in aging, memory, depression, and anxiety. To determine how products of cap-dependent translation play a permissive role in aged-associated inflammation, we assessed levels of pro-inflammatory cytokines in various brain regions involved in the above-mentioned behaviors. We found that functional eIF4E is not necessary for age-related deficits in spatial and short-term memory but is important for depressive and anxiety-like behavior and this is correlated with pro-inflammatory cytokines in discrete brain regions. Thus, we have begun to elucidate a role for eIF4E phosphorylation in the context of aged-related behavioral impairments and chronic low-grade inflammation that may help identify novel immune modulators for therapeutic targets and decrease the burden of self-care among the geriatric population.
Learn More >Most studies examining the components of the fear-avoidance model have examined processes at the group level. The current study used ecological momentary assessments to: (a) investigate the group and intraindividual relationships between pain fear, avoidance, and pain severity, (b) identify any heterogeneity between these relationships, and (c) explore the role of moderators to explain such heterogeneity.
Learn More >The co-occurrence of headache and epilepsy is well-documented in the adult population. The aim of the prospective study was to analyse in the paediatric population the correlations between the types of peri-ictal headaches and types of seizures. Furthermore, an attempt was made to find trends in characteristic features of peri-ictal headaches. A total of 57 children with peri-ictal headache were enrolled in the study. The participants' guardians were asked to keep a diary of the seizure and peri-ictal headache episodes during a 180-day period. During follow-up visits, systematic history regarding peri-ictal headaches was taken.
Learn More >Voltage-gated sodium channels (Navs) are promising targets for analgesic and antiepileptic therapies. Although specificity between Nav subtypes may be desirable to target specific neural types, such as nociceptors in pain, many broadly acting Nav inhibitors are clinically beneficial in neuropathic pain and epilepsy. Here, we present the first systematic characterization of vixotrigine, a Nav blocker. Using recombinant systems, we find that vixotrigine potency is enhanced in a voltage- and use-dependent manner, consistent with a state-dependent block of Navs. Furthermore, we find that vixotrigine potently inhibits sodium currents produced by both peripheral and central nervous system Nav subtypes, with use-dependent IC values between 1.76 and 5.12 μM. Compared with carbamazepine, vixotrigine shows higher potency and more profound state-dependent inhibition but a similar broad spectrum of action distinct from Nav1.7- and Nav1.8-specific blockers. We find that vixotrigine rapidly inhibits Navs and prolongs recovery from the fast-inactivated state. In native rodent dorsal root ganglion sodium channels, we find that vixotrigine shifts steady-state inactivation curves. Based on these results, we conclude that vixotrigine is a broad-spectrum, state-dependent Nav blocker. SIGNIFICANCE STATEMENT: Vixotrigine blocks both peripheral and central voltage-gated sodium channel subtypes. Neurophysiological approaches in recombinant systems and sensory neurons suggest this block is state-dependent.
Learn More >Physical exercise has been established as a low-cost, safe, and effective way to manage chronic pain, but exact mechanisms underlying such exercise-induced hypoalgesia (EIH) are not fully understood. Since a growing body of evidence implicated the amygdala (Amyg) as a critical node in emotional affective aspects of chronic pain, we hypothesized that the Amyg may play important roles to produce EIH effects. Here, using partial sciatic nerve ligation (PSL) model mice, we investigated the effects of voluntary running (VR) on the basal amygdala (BA) and the central nuclei of amygdala (CeA). The present study indicated that VR significantly improved heat hyperalgesia which was exacerbated in PSL-Sedentary mice, and that a significant positive correlation was detected between total running distances after PSL-surgery and thermal withdrawal latency. The number of activated glutamate (Glu) neurons in the medal BA (medBA) was significantly increased in PSL-Runner mice, while those were increased in the lateral BA in sedentary mice. Furthermore, in all subdivisions of the CeA, the number of activated gamma-aminobutyric acid (GABA) neurons was dramatically increased in PSL-Sedentary mice, but these numbers were significantly decreased in PSL-Runner mice. In addition, a tracer experiment demonstrated a marked increase in activated Glu neurons in the medBA projecting into the nucleus accumbens lateral shell in runner mice. Thus, our results suggest that VR may not only produce suppression of the negative emotion such as fear and anxiety closely related with pain chronification, but also promote pleasant emotion and hypoalgesia. Therefore, we conclude that EIH effects may be produced, at least in part, via such plastic changes in the Amyg.
Learn More >A chronic pain patient sample living in the United States who participated in a cross-sectional study to evaluate the validity and reproducibility of the Prescription Opioid Misuse and Abuse Questionnaire is characterized.
Learn More >Atopic dermatitis (AD) is a relapsing and remitting disease characterized by intense pruritus that can lead to scratching and eczematous lesions that vary in extent and severity . Over 60% of AD cases are mild, characterized by slight erythema, induration, and lichenification . Chronic pruritus, pruritus lasting more than 6 weeks, has been reported by 91% of AD patients . The pathophysiology of AD is driven by a combination of skin barrier dysfunction, neuroinflammation, and immune system dysregulation .
Learn More >There is neither strong evidence on effective treatments for patients with chronic back pain (CBP) and depressive disorder nor sufficiently available mental health care offers.
Learn More >Several factors are known to impact response to the intensive interdisciplinary pain treatment (IIPT) program described in this study, yet no research has explored the role of perfectionism. This secondary data analysis explored direct and indirect relations between perfectionism and functional disability (primary outcome) and pain severity (secondary outcome) after IIPT, with pain catastrophizing and fear of pain as mediators.
Learn More >Cancer and cancer treatment-related chronic pain affect a significant number of patients. The etiology of this pain is diverse and may include nociceptive and/or neuropathic characteristics. Treatment is often multifactorial and may require advanced interventional techniques, such as spinal cord stimulation (SCS). This narrative review provides a thorough overview of cancer-related pain mechanisms and the use of SCS for cancer-related pain. Additionally, a review of the precautions that should be considered when caring for this patient population is provided with recommendations for safe care when utilizing these techniques.
Learn More >Previous studies have proved that observational learning can induce placebo analgesia, but the factors that influence observationally induced placebo analgesia have not yet been extensively examined. The primary goal of this study was to investigate the effect of information about the role that the observed person (model) plays in the experiment on the magnitude of the observationally induced placebo effect. This study also examined the contribution of the observer's empathy, conformity and fear of pain to the placebo analgesia induced by observational learning. The effects induced in two experimental groups and one control group were compared. Participants in the experimental groups observed a model introduced as either another participant taking part in the study or a coworker of the experimenter. The model rated the intensity of pain induced by electrocutaneous stimuli preceded by color stimuli. One-half of all participants watched a model rating pain stimuli preceded by the color orange as higher than stimuli preceded by the color blue; for the other half, the ratings were the opposite. There was no observation in the control group. Subsequently, all participants received pain stimuli of the same intensity preceded by orange and blue stimuli and rated the intensity of the experienced pain. Placebo analgesia was found in both experimental groups. However, the way the observed model was introduced to participants did not affect the magnitude of placebo analgesia. Thus, the study showed that the role played by the model is not crucial for observationally induced placebo analgesia. The examined observer's individual characteristics did not predict the magnitude of placebo effect.
Learn More >Oxytocin receptor (OXTR), a G protein-coupled receptor, has been demonstrated to play a significant role in analgesia after activation by its canonical agonist, oxytocin (OXT) in the dorsal root ganglion (DRG). However, the role of OXTR in the trigeminal nervous system on the orofacial neuropathic pain is still little known. In the present study, we aimed to investigate the regulation effect and mechanism of OXTR in the trigeminal ganglion (TG) and spinal trigeminal nucleus caudalis (SpVc) on orofacial ectopic pain induced by trigeminal nerve injury. Inferior alveolar nerve (IAN) was transected to establish trigeminal ectopic pain model. Von Frey filaments behavioral test demonstrated IAN transection (IANX) evoked mechanical hypersensitivity in the whisker pad since from day 1 to at least day 14 after surgery. In addition, administration of OXT (50 μM and 100 μM) into the TG attenuated the mechanical hypersensitivity induced by IANX, which was reversed by pre-treatment with L-368,899 (a selective antagonist of OXTR) into the TG. In addition, immunofluorescence (IF) showed the expression of OXTR in neurons in the TG and SpVc. Furthermore, western blot (WB) analysis indicated that the upregulated expression of OXTR, calcitonin gene-related peptide (CGRP), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the TG and SpVc after IANX was inhibited by the administration of OXT into the TG. And the inhibition effect of OXT on the expression of CGRP, IL-1β, and TNF-α was abolished by pre-application of L-368,899 into the TG.
Learn More >Chronic refractory central post-stroke pain (CPSP), one of the most disabling consequences of cerebral stroke, occurs in up to 10% of patients with CPSP. Because a considerable proportion of these patients with chronic pain remain resistant to pharmacological and behavioral therapies, adjunctive invasive and non-invasive brain stimulation therapies are needed. We performed a review of human studies applying burst and conventional motor cortex stimulation (burstMCS and cMCS, respectively) for chronic pain states, on the basis of data sources identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, as well as manual searches of the bibliographies of known primary and review articles. Our aim was to review and discuss clinical data on the indications of burstMCS for various chronic pain states originating from central stroke (excluding trigeminal facial pain). In addition, we assessed the efficacy and safety of burst versus cMCS for central post-stroke pain with an extended follow-up of 5 years in a 60-year-old man. According to our review, uncontrolled observational human cohort studies and one RCT using cMCS waveforms have revealed a meaningful clinical response; however, these studies lacked placebo groups and extended observation periods. In our case report, we found that 3 months of adjunctive cMCS reduced pain levels [visual analog scale (VAS) pre: 9/10 versus VAS post 7/10], whereas the pain decreased further under burstMCS (VAS pre: 7/10 versus VAS post: 2/10); the study involved a follow-up of 5 years and the following parameters: burst rate 40 Hz (500 Hz), 1-1.75 mA, 1 ms, bipolar configuration. To date, only limited evidence exists for the efficacy and safety of burst motor cortex stimulation for the treatment of refractory chronic pain. BurstMCS resulted in significantly decreased post-stroke pain observed after 5 years of cMCS. The available literature suggests similar efficacy as that of conventional (tonic) motor cortex stimulation, although the results are preliminary. Mechanistically, the precise mechanism of action is not fully understood. However, burstMCS may interact with the nociceptive thalamic-cingulate and descending spinal pain networks. To determine the potential utility of this treatment, large-scale sham-controlled trials comparing cMCS and burstMCS are highly recommended.
Learn More >Monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor (Erenumab) or against CGRP (Eptinezumab, Fremanezumab, Galcanezumab) are new substances for the preventive treatment of migraine. They represent an extension of the therapeutic options, which already exist in migraine prevention. In randomized, placebo-controlled studies, the efficacy and good tolerability of these specific substances have been demonstrated in patients with episodic and chronic migraine. The following treatment recommendation presents a summary of the pivotal studies. Recommendations are provided for the targeted selection of patients as well as for the evaluation of therapeutic success and the duration of treatment. Finally, possible restrictions on the use of this new substance group are discussed. This guideline is an abridged and translated version of the guideline published by Diener H-C, May A et al., Prevention of migraine with monoclonal antibodies against CGRP or the CGRP receptor, Supplement to S1 Guideline Therapy of Migraine Attack and Prevention of Migraine, 2019, Deutsche Gesellschaft für Neurologie (eds.), Guidelines for Diagnostics and Therapy in Neurology. A complete version of this guideline can be found on the website of the Deutsche Gesellschaft für Neurologie (www.dgn.org/leitlinien) and the AWMF (Arbeitsgemeinschaft wissenschaftlicher Medizinischer Gesellschaften). This guideline has been approved by the German Neurological Society (DGN) and the German Migraine and Headache Society (GMHS) and was reviewed by the two societies.
Learn More >To study differences in pain reports between patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA), and to assess how pain sensitivity measures associate with disease and health outcomes.
Learn More >Managing chronic musculoskeletal problems usually focuses on pain control using medications, but outcomes are often unsatisfactory and sometimes harmful. Information on a patient's health-related quality of life (HRQOL) may trigger a doctor to tailor management improving quality of life. The aim of this trial is to find out whether routine measurement and reporting of a patient's EuroQoL 5-Dimension 5-Level (EQ-5D-5L) HRQOL data using an electronic platform can improve HRQOL and pain in patients with chronic knee or back problems in primary care. We will also assess the acceptability of routine electronic measurements and reporting of the EQ-5D-5L in primary care settings.
Learn More >Ion channels underlie all forms for electrical signaling including the transmission of information about harmful events. Voltage-gated calcium ion channels have dual function, they support electrical signaling as well as intracellular calcium signaling through excitation-dependent calcium entry across the plasma membrane. Mechanisms that regulate ion channel forms and actions are essential for myriad cell functions and these are targeted by drugs and therapeutics. When disrupted, the cellular mechanisms that control ion channel activity can contribute to disease pathophysiology. For example, alternative pre-mRNA splicing is a major step in defining the precise composition of the transcriptome across different cell types from early cellular differentiation to programmed apoptosis. An estimated 30% of disease-causing mutations are associated with altered alternative splicing, and mis-splicing is a feature of numerous highly prevalent diseases including neurodegenerative, cancer, and chronic pain. Here we discuss the important role of epigenetic regulation of gene expression and cell-specific alternative splicing of calcium ion channels in nociceptors, with emphasis on how these processes are disrupted in chronic pain, the potential therapeutic benefit of correcting or compensating for aberrant ion channel splicing in chronic pain.
Learn More >Preemptive management of post-incisional pain remains challenging. Here, we examined the role of preemptive use of neuroactive steroids with activity on low-voltage activated T-type Ca channels (T-channels) and γ-aminobutyric acid A (GABA) receptors in the development and maintenance of post-incisional pain. We use neuroactive steroids with distinct effects on GABA receptors and/or T-channels: Alphaxalone (combined GABAergic agent and T-channel inhibitor), ECN (T-channel inhibitor), CDNC24 (GABAergic agent), and compared them with an established analgesic, morphine (an opioid agonist without known effect on either T-channels or GABA receptors). Adult female rats sustained the skin and muscle incision on the plantar surface of the right paw. We injected the agents of choice intrathecally either before or after the development of post-incisional pain. The pain development was monitored by studying mechanical hypersensitivity. Alphaxalone and ECN, but not morphine, are effective in alleviating mechanical hyperalgesia when administered preemptively whereas morphine provides dose-dependent pain relief only when administered once the pain had developed. CDNC24 on the other hand did not offer any analgesic benefit. Neuroactive steroids that inhibit T-currents-Alphaxalone and ECN-unlike morphine, are effective preemptive analgesics that may offer a promising therapeutic approach to the treatment of post-incisional pain, especially mechanical hypersensitivity.
Learn More >Chronic musculoskeletal disorders are the second largest contributor to disability globally. Exercise is typically recommended by physiotherapists to manage symptoms. However, adherence to the prescribed exercise programme is often poor. Adjunctive digital interventions offer potential to enhance exercise adherence.
Learn More >Despite decades of research on the identification of specific characteristics of situations that trigger a physiological stress response (novelty, unpredictability, threat to the ego, and sense of low control [NUTS]), no integrative research has examined the validity of this framework applied to pain experiences. This study aimed to 1) explore the stressful characteristics of pain among individuals living with chronic pain and 2) examine whether the NUTS framework comprehensively captures the stressful nature of pain.
Learn More >Chronic pain is a significant public health problem associated with functional impairment, increased medical expenditures, and opioid misuse. Recent work has suggested that certain transdiagnostic psychosocial factors may be more important than pain intensity to better understand pain and opioid outcomes. Specifically, pain-related anxiety, anxiety sensitivity, emotion dysregulation, and distress tolerance have all been uniquely associated with both pain and opioid outcomes across a range of samples. Yet, no work has examined how these transdiagnostic constructs relate to pain and opioid misuse when accounting for the other constructs. Therefore, the current study employed two independent sample of adults with chronic pain to examine (1) the construct independence of each of these factors using exploratory structural equation modelling (ESEM) and (2) how each of these constructs relates to pain and opioid outcomes in latent structural models. Results from Study 1 provided empirical support for construct independence of the transdiagnostic constructs. Findings from Study 2 indicated that pain-related anxiety was most strongly related to pain intensity, interference, and pain-related negative affect, anxiety sensitivity with opioid misuse, and emotion dysregulation with all studied criterion variables. The current results highlight the importance of assessing and targeting transdiagnostic constructs among adults with pain.
Learn More >To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300 mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication-overuse headache (MOH).
Learn More >To compare the prevalence of psychiatric comorbidity between patients with complex regional pain syndrome (CRPS) of the hand and non-CRPS patients and to assess the association between biopsychosocial (BPS) complexity profiles and psychiatric comorbidity in a comparative study.
Learn More >Chronic lower back pain is a highly prevalent medical condition in Western countries, which that incurs a considerable social and economic burden. Although prescription exercise at home for chronic pain has become a widely used alternative to reduce healthcare costs, the evidence regarding patient adherence and decreased in costs in European countries is scarce and inconclusive. The objective of this study is to examine the cost-utility and cost-effectiveness in patients with chronic lower back pain treated with the McKenzie Method and electroanalgesia via a telemedicine programme versus a face-to-face programme.
Learn More >Myofascial pain syndrome (MPS) is a prevalent chronic pain disorder primarily characterized by myofascial trigger points (MTrPs). There is limited knowledge on the pathophysiology and mechanisms underlying MTrP and its development. Research has previously demonstrated the identification of MTrPs using ultrasound and vibration sonoelastography, although there is some contradictory evidence regarding if MTrPs present as hyper or hypoechoic regions. Electromyography (EMG) investigations of MTrP have demonstrated that MTrPs are usually located proximal to innervation zones where the peak surface EMG signals are obtained from. Central sensitization has been proposed as the primary mechanism underlying MTrP development. Central sensitization is associated with hyperexcitability of neuronal responses to normal or noxious stimuli. There is a need for a study that measures ultrasound image textural changes and motor unit activity responses in the muscle following sensitization. The purpose of this study is to determine whether sensitizing healthy muscle using capsaicin induces a regional change in image texture variables within the specific and surrounding muscles, as well as the motor unit frequency and amplitude changes that accompany them. This is an exploratory trial that aims to provide preliminary evidence on whether central sensitization is a direct cause of taut band and MTrP development.
Learn More >Several neuromodulation methods exists for migraine treatment. The aim of the present study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) focusing on migraine treatment using neurostimulation methods.
Learn More >Headache mobile health (mHealth) applications (apps) have gained popularity in use but there is little research into what people with migraine find important to track. This information is important for helping with adherence and determining meaningful data to patients. We conducted several clinical trials using a headache research app (RELAXaHEAD). The app contains a "notes" feature (a free-text input section) where patients could record notes related to their headache.
Learn More >Previous studies suggested that Cg1 area of the cingulate cortex of rats controls glutamate-mediated fear-induced defensive behaviour and antinociception organised at the posterior hypothalamus. In turn, microinjection of the nitric oxide donor SIN-1 into the anterior hypothalamus of mice produced defensive behaviours and fear-induced antinociception. However, it remains unknown whether Cg1 also modulates the latter mechanisms in mice.
Learn More >Expectation affects pain experience in humans. Numerous studies have reported that pre-stimulus activity in the anterior insular cortex (aIC), together with prefrontal and limbic regions, integrated pain intensity and expectations. However, it is unclear whether the resting-state functional connectivity (rs-FC) between the aIC and other brain regions affects chronic pain. The purpose of this study was to examine the rs-FC between the aIC and the whole brain regions in female patients with severe knee osteoarthritis (OA).
Learn More >Neuropathic pain (NP) is frequent in neuromyelitis optica spectrum disorders (NMOSD). The ventral posterior nucleus (VPN) of the thalamus receives sensory afferences from the spinothalamic tracts and is associated with central pain in other conditions.
Learn More >As psychosocial factors have been recognised as significant predictors of the recovery trajectory from chronic back pain, the 34-item Back Pain Attitudes Questionnaire (Back-PAQ) was developed based on themes obtained from patient interviews, but previous psychometric analyses with a general population sample revealed uncertainty around the factor structure of the instrument.
Learn More >ASP0819 is a novel, non-opioid K3.1 channel opener that reverses abnormal nerve firing of primary sensory afferent nerves. Currently available treatments for fibromyalgia provide only modest relief and are accompanied by a host of adverse side effects.
Learn More >Pain has been associated with structural changes of the brain. However, evidence regarding white matter changes in response to acute pain protocols is still scarce. In the present study, we assess the existence of differences in brain white matter related to pain intensity reported by patients undergoing surgical removal of a mandibular impacted third molar using diffusion tensor imaging (DTI) analysis. 30 participants reported their subjective pain using a visual analog scale at three postsurgical stages: under anesthesia, in pain, and after the administration of an analgesic. The diffusion data were acquired prior to surgery. DTI analysis yielded significant positive associations of fractional anisotropy in white matter areas related to pain processing (corticospinal tract, corona radiata, corpus callosum) with the differences in pain between the three postsurgery stages. Extent and location of these associations depended on the magnitude of the subjective pain differences. Tractography analysis indicated that some pain-tract associations are significant only when pain stage is involved in the contrast (posterior corona radiata), while others (middle cerebellar peduncle, pontine crossing) are only when anesthesia is involved in the contrast. The association of white matter fractional anisotropy and connectivity, measured before the pain stages, with subjective pain depends on the magnitude of the differences in pain scores.
Learn More >Pain and cartilage destruction caused by rheumatoid arthritis (RA) are major challenges during clinical treatment. Traditional systemic administration not only has obvious side effects but also provides limited relief for local symptoms in major joints. Local delivery of therapeutics for RA treatment is a potential strategy but is limited by rapid intraarticular release.
Learn More >To investigate whether cross-sectional and longitudinal associations of body mass index (BMI) and waist circumference (WC) with back pain change with age and extend into later life.
Learn More >Nerve injury-induced pain is difficult to treat. In this study, we developed an alginate scaffold with human umbilical cord mesenchymal stem cell exosomes (EX-SC) to treat nerve injury-induced pain.
Learn More >To systematically review the effectiveness of manual therapy on fear-avoidance, kinesiophobia, and pain catastrophizing in patients with chronic musculoskeletal pain.
Learn More >(1) Background: Chronic musculoskeletal pain (CMP) in adolescents can negatively affect physical, psychological, and social functioning, resulting in functional disability. This randomized controlled trial (RCT) aimed to evaluate the effectiveness of an outpatient rehabilitation program based on graded exposure in vivo (EP) compared with care as usual (CAU: interdisciplinary outpatient rehabilitation care). Both EP and CAU aim to improve functional ability in adolescents with CMP. (2) Methods: Pragmatic multicenter RCT with 12-month follow-up. Adolescents (12-21 years) with CMP were invited to participate. Primary outcome: functional disability; secondary outcomes: perceived harmfulness; pain catastrophizing; pain intensity. Data analysis: intention-to-treat linear mixed model. (3) Results: Sixty adolescents (mean 16 years) were randomized; data for 53 were analyzed. Adolescents in EP showed relevant and significant decreases in functional disability (estimated mean difference at least -8.81, ≤ 0.01) compared with CAU at all times. Significant differences in favor of EP were found for perceived harmfulness at all times ( ≤ 0.002), for pain catastrophizing at 2 months ( = 0.039) and for pain intensity at 4 and 10 months ( ≤ 0.028). (4) Conclusion: EP leads to a significant and clinically relevant decrease in functional disability compared with usual care.
Learn More >This study aimed to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effects of cytotoxic T lymphocyte-associated antigen-4Ig (CTLA-4Ig) administration in ovariectomized (OVX) mice. Eight-week-old female ddY mice were assigned to three groups: sham-operated mice (SHAM) treated with vehicle, OVX mice treated with vehicle (OVX), and OVX mice treated with CTLA-4Ig (CTLA-4Ig). Vehicle or CTLA-4Ig was injected intraperitoneally, starting immediately after surgery. After 4 weeks of treatment, mechanical sensitivity was examined, and the bilateral hind limbs were removed and evaluated by micro-computed tomography, immunohistochemical analyses, and messenger RNA expression analysis. Ovariectomy induced bone loss and mechanical hyperalgesia in the hindlimbs. CTLA-4Ig treatment prevented bone loss in the hindlimbs compared to vehicle administration in the OVX group. Moreover, mechanical hyperalgesia was significantly decreased in the CTLA-4Ig treatment group in comparison to the OVX group. The expression levels of tumor necrosis factor-α (TNF-α) and sclerostin (SOST), as well as the number of osteoclasts, were increased, and the expression level of Wnt-10b was decreased in the OVX group compared with the SHAM group, whereas these parameters were improved in the CTLA-4Ig group compared with the OVX group. The novelty of this research is that CTLA-4Ig administration prevented bone loss and mechanical hyperalgesia induced by ovariectomy in the hindlimbs.
Learn More >Chronic pain is considered a public health priority by the World Health Organization and European health institutions. It has reached alarming proportions in terms of disability, consumption of health and social resources, and impact on primary and specialist care services. Primary care physicians are often called on to manage this condition. Chronic pain management can be challenging due to its complexity. It has traditionally been considered to include nociceptive pain that that persists longer than the normal healing time, neuropathic pain lasting more than 3 months, or a combination of these. More recently, a third descriptor, nociplastic (primary) pain, was added to classify patients with chronic pain conditions such as fibromyalgia, nonspecific back pain, or mixed pain that persists or other conditions in which altered central pain modulation results in central sensitization and chronic pain in the absence of actual or threatened damage to tissues, including in the somatosensory nervous system. This document provides an overview of pain types and their underlying mechanisms. Successful pain management is facilitated by identification of the pain type. A set of diagnostic tools and a pain algorithm are presented to guide the clinician toward the correct diagnosis. The algorithm identifies cases that may require referral to a pain specialist. Once the site of origin of the pain (the "pain generator") is identified, or a primary pain syndrome is suspected, the accompanying article provides information and rationale to support treatment decisions based on patient characteristics.
Learn More >Many health care systems are beginning to encourage patients to use complementary and integrative health (CIH) therapies for pain management. Many clinicians have anecdotally reported that patients combining self-care CIH therapies with practitioner-delivered therapies report larger health improvements than do patients using practitioner-delivered or self-care CIH therapies alone. However, we are unaware of any trials in this area.
Learn More >In this study, we investigated the relationship between sensory abnormalities evaluated by quantitative sensory testing (QST) and alexithymia, depression and anxiety in patients with neuropathic pain involving the upper limbs. We enrolled 62 patients (34 with carpal tunnel syndrome, 7 with brachial plexopathy, 3 with cervical painful radiculopathy, 5 with ulnar entrapment neuropathy at elbow and 13 with post-burn hypertrophic scars) and 48 healthy controls. All underwent nerve conduction studies (NCS), evaluation of cold, heat pain and vibration detection threshold (VDT) by QST and evaluation of alexithymia by Toronto Alexithymia Scale (TAS-20), depression by Beck Depression Inventory II (BDI-II), anxiety by State-Trait Anxiety Inventory (STAI-Y), level of psychological distress by 12-item General Health Questionnaire (GHQ-12) and perceived social support by the Multidimensional Scale of Perceived Social Support (MSPSS). The general linear model analysis revealed a significant relationship between TAS-20 overall and TAS-20 sub-score for difficulty identifying feelings and VDT z-scores in the left index with no interaction by year of education and sensory NCS results. Our results demonstrated the association between impairment of vibratory sensation of the left hand, reflecting cutaneous mechanoceptor dysfunction, and alexithymia, particularly the difficulty to identify feelings. The importance of delivering to patients with neuropathic pain personalized care that takes into account not only the neurophysiological aspects but also the aspects of mental functioning is discussed.
Learn More >The Whole Health model of the U.S. Department of Veterans Affairs (VA) emphasizes holistic self-care and multimodal approaches to improve pain, functioning, and quality of life. wHOPE (Whole Health Options and Pain Education) seeks to be the first multisite pragmatic trial to establish evidence for the VA Whole Health model for chronic pain care.
Learn More >Given access barriers to cognitive behavioral therapy for chronic pain (CBT-CP), this pragmatic superiority trial will determine whether a remotely delivered CBT-CP intervention that addresses these barriers outperforms in-person and other synchronous forms of CBT-CP for veterans with musculoskeletal pain.
Learn More >Low back pain is a leading cause of disability in veterans. Chiropractic care is a well-integrated, nonpharmacological therapy in Veterans Affairs health care facilities, where doctors of chiropractic provide therapeutic interventions focused on the management of low back pain and other musculoskeletal conditions. However, important knowledge gaps remain regarding the effectiveness of chiropractic care in terms of the number and frequency of treatment visits needed for optimal outcomes in veterans with low back pain.
Learn More >Veterans with significant chronic pain from musculoskeletal disorders are at risk of substance misuse. Veterans whose condition is the result of military service may be eligible for a disability pension. Department of Veterans Affairs compensation examinations, which determine the degree of disability and whether it was connected to military service, represent an opportunity to engage Veterans in pain management and substance use treatments. A multisite randomized clinical trial is testing the effectiveness and cost-effectiveness of Screening, Brief Intervention, and Referral to Treatment for Pain Management (SBIRT-PM) for Veterans seeking compensation for musculoskeletal disorders. This telephone-based intervention is delivered through a hub-and-spoke configuration.
Learn More >Mindfulness-based interventions (MBIs) are evidence-based nonpharmacological treatments for treating chronic pain. However, the predominant MBI, mindfulness-based stress reduction, has features that pose significant implementation barriers.
Learn More >Percutaneous peripheral nerve stimulation (PNS) is an analgesic modality involving the insertion of a lead through an introducer needle followed by the delivery of electric current after needle withdrawal. This modality has been used extensively to treat chronic pain, but only small series have been published involving postoperative pain. The ultimate objective of this study is to determine the postoperative effects of percutaneous PNS following moderately to severely painful ambulatory surgery within a real-world clinical practice setting. The primary hypothesis is that surgical pain and opioid consumption during the initial 7 days after surgery will be reduced by percutaneous PNS compared with usual and customary analgesia (dual primary outcome measures).
Learn More >Manualized cognitive and behavioral therapies are increasingly used in primary care environments to improve nonpharmacological pain management. The Brief Cognitive Behavioral Therapy for Chronic Pain (BCBT-CP) intervention, recently implemented by the Defense Health Agency for use across the military health system, is a modular, primary care-based treatment program delivered by behavioral health consultants integrated into primary care for patients experiencing chronic pain. Although early data suggest that this intervention improves functioning, it is unclear whether the benefits of BCBT-CP are sustained. The purpose of this paper is to describe the methods of a pragmatic clinical trial designed to test the effect of monthly telehealth booster contacts on treatment retention and long-term clinical outcomes for BCBT-CP treatment, as compared with BCBT-CP without a booster, in 716 Defense Health Agency beneficiaries with chronic pain.
Learn More >The Defense Health Agency has prioritized system-level pain management initiatives within the Military Health System (MHS), with low back pain as one of the key focus areas. A stepped care model focused on nonpharmacologic treatment to promote self-management is recommended. Implementation of stepped care is complicated by lack of information on the most effective nonpharmacologic strategies and how to sequence and tailor the various available options. The Sequential Multiple-Assignment Randomization Trial for Low Back Pain (SMART LBP) is a multisite pragmatic trial using a SMART design to assess the effectiveness of nonpharmacologic treatments for chronic low back pain.
Learn More >Based on the adverse consequences and inadequate evidence of effectiveness for long-term opioid therapy (LOT), the CDC developed recommendations to decrease the use of LOT and morphine equivalent dose (MED) for patients receiving LOT. However, the majority of these patients report that opioid medication is significantly beneficial for pain management and are hesitant to reduce/decrease its use. Compounding the problem is poor access to non-pharmacologic therapies for many patients due to insurance reimbursement structures and limited pain-service availability. EMPOWER is an intent-to-treat, two-arm, open-label, randomized controlled trial evaluating a web-based self-management chronic pain program (E-health) that has been found to reduce self-reported MED, while also decreasing pain, in two randomized controlled trials. Approximately 400 chronic pain patients receiving LOT at a daily average prescribed MED ≥ 20 mg at one of two U.S. healthcare systems, located in North Carolina and Ohio, will be randomized in a 1:1 ratio to treatment as usual (TAU) or TAU plus E-health (E-health). TAU consists of LOT from a prescribing clinician. E-health participants are provided with a 4-month E-health subscription (active treatment phase). All participants will complete web-based self-report measures at baseline, the end of the active treatment phase, and 6-months post-active treatment. Opioid prescription information will be collected from the participants' electronic health record (EHR) from baseline through 6 months post-active treatment. This paper describes design considerations for this unique trial which is conducted completely remotely, with no in-person visits, and utilizes the EHR for participant identification and primary outcome collection.
Learn More >Heteromers between mu opioid receptor (MOPr) and delta opioid receptor (DOPr) (i.e., MOPr-DOPr heteromer) have been found to be expressed in different brain regions, in the spinal cord, and in dorsal root ganglia. Recent studies on this heteromer reveal its important pathophysiological function in pain regulation including neuropathic pain; this suggests a role as a novel therapeutic target in chronic pain management. In addition, receptor transporter protein 4 (RTP4) has been shown to be involved in the intracellular maturation of the MOPr-DOPr heteromers. RTP4 appears to have unique distribution being highly expressed in sensory neurons and also macrophages; the latter are effector cells of the innate immune system that phagocytose foreign substances and secrete both pro-inflammatory and antimicrobial mediators; this suggests a possible contribution of RTP4 to neuronal immune-related pathological conditions such as neuropathic pain. Although RTP4 could be considered as an important therapeutic target in the management of pain via MOPr-DOPr heteromer, a few reports have supported this. This review will summarize the possible role or functions of the MOPr-DOPr heteromer and its regulatory molecule RTP4 in pain modulation at sensory neurons.
Learn More >Postherpetic neuralgia (PHN) is the most common complication attributed to herpes zoster, which involves the reactivation of residual varicella zoster virus. It has been reported previously that pre-emptive amitriptyline following acute herpes zoster has shown latent positive effects in the prevention of PHN. In this study, by interfering with the same targets, norepinephrine and serotonin, we aim to evaluate whether pre-emptive duloxetine may proactively prevent PHN development.
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