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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 >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 >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 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 >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 >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 >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 >(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 >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 >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.
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