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To investigate whether the two briefest validated ICF-based (International Classification of Functioning, Disability and Health) tools can detect differences between different spinal conditions.
Learn More >Therapeutic interventions for neuropathic pain (NP), such as the NMDA-antagonist ketamine, can vary widely in effectiveness; Here, we conducted a longitudinal functional MRI study to test the hypothesis that the pain relieving effect of ketamine is due to reversal of abnormalities in regional low frequency brain oscillations (LFOs) and abnormal cross-network functional connectivity (FC) of the dynamic pain connectome. We found that: 1) ketamine decreased regional LFOs in the posterior cingulate cortex (PCC) of the default mode network (DMN), 2) a machine learning algorithm demonstrated that treatment-induced brain changes could be used to make generalizable inferences about pain relief, 3) treatment responders exhibited a significant decrease in cross-network static FC between the PCC and regions of the sensorimotor (SM) and salience networks following treatment, 4) the degree of reduced cross-network FC was correlated with the amount of pain relief, and 5) ketamine treatment did not produce significant differences in static or dynamic FC within the ascending nociceptive- or descending antinociceptive pathway. These findings support the proposition that regional LFOs contribute to cross-network connectivity that underlie the effectiveness of ketamine to produce significant relief of neuropathic pain. Together with our recent findings that pre-treatment dynamic FC of the descending antinociceptive pathway can predict ketamine treatment outcomes, these new findings indicate that pain relief from ketamine arises from a combination of a strong and flexible pre-treatment FC of the descending antinocieptive pathway together with plasticity (reduction) of cross-network connectivity of the DMN with SM and salience networks.
Learn More >The purpose of this randomized controlled trial is to determine whether the quantity of opioid pills prescribed at discharge is associated with the number of opioid pills consumed or unused by patients after primary hip and knee arthroplasty within 30 days after discharge.
Learn More >The opioid risk tool (ORT) is a commonly employed measure of risk of aberrant drug related behaviors (ADRB) in patients with chronic pain prescribed opioid therapy. In this study the discriminant predictive validity of the ORT was evaluated in a unique cohort of patients with chronic nonmalignant pain (CNMP) on long-term opioid therapy (LTOT) that displayed no evidence of developing an opioid use disorder (OUD) and a sample of patients with CNMP that developed an OUD after commencing opioid therapy. Results revealed that the original ORT was able to discriminate between patients with and without OUDs (OR=1.624; CI 95%: 1.539-1.715, p< 0.001). A weighted ORT eliminating the gender specific history of preadolescent sexual abuse item revealed comparable results (OR= 1.648; CI 95%: 1.539-1.742, p< 0.001). A revised unweighted ORT (ORT-OUD) removing the history of preadolescent sexual abuse item was notably superior in predicting the development of OUD in patients with CNMP on LTOT (OR= 3.085; CI 95%: 2.725-3.493, p< 0.001) with high specificity (0.851; CI 95%: 0.811-0.885), sensitivity (0.854; 95% CI: 0,799-0.898), positive (0.757; CI 95%: 0.709-0.799) and negative (0.914; CI 95%: 0.885-0.937) predictive values. Perspective: The revised ORT (ORT-OUD) is the first tool developed on a unique cohort to predict the risk of developing an OUD in patients with CNMP receiving opioid therapy, as opposed to ADRB that can reflect a number of other issues. The ORT-OUD has clinical utility in providing clinicians a simple, validated method to rapidly screen for the risk of developing OUD in patients on or being considered for opioid therapy.
Learn More >Fabry disease (FD) is an X-linked lysosomal storage disorder associated with pain triggered by heat or febrile infections. We modelled this condition by measuring the cytokine expression of peripheral blood mononuclear cells (PBMC) from FD patients in vitro upon stimulation with heat and lipopolysaccharide (LPS). We enrolled 67 FD patients and 37 healthy controls. We isolated PBMC, assessed their gene expression of selected pro- and anti-inflammatory cytokines, incubated them with heat, LPS, globotriaosylceramide (Gb3), and tumor necrosis factor-α (TNF), and measured TNF secretion in the supernatant and intracellular Gb3 accumulation, respectively. We found increased TNF, interleukin (IL-)1β, and toll-like receptor 4 (TLR4) gene expression in FD men (p < .05 to p < .01). TNF and IL-10 were higher, and IL-4 was lower in the subgroup of FD men with pain compared to controls (p < .05 to p < .01). Hereby, TNF was only increased in FD men with pain and classical mutations (p < .05) compared to those without pain. PBMC from FD patients secreted more TNF upon stimulation with LPS (p < .01) than control PBMC. Incubation with Gb3 and an additional α-galactosidase A inhibitor did not further increase TNF secretion, but incubation with TNF greatly increased the Gb3 load in FD PBMC compared to controls (p < .01). Also, LPS incubation and heat challenge (40 °C) increased Gb3 accumulation in PBMC of patients compared to baseline (p < .05 each), while no alterations were observed in control PBMC. Our data show that TNF holds a crucial role in the pathophysiology of FD associated pain, which may open a novel perspective for analgesic treatment in FD pain.
Learn More >Internalizing mental health issues co-occur with pediatric chronic pain at high rates and are linked to worse pain and functioning. Although the field has prioritized anxiety and posttraumatic stress disorder, little is known about co-occurring depression and chronic pain in youth, despite its high prevalence. The purpose of this narrative review was to examine the existing literature on the co-occurrence of pediatric chronic pain and depressive disorders and symptoms and propose a conceptual model of mutual maintenance to guide future research.
Learn More >Since the definition of chronic migraine as a new disease entity in 2004, numerous clinical trials have examined the efficacy of preventive treatments in chronic migraine. Our aim was to assess the adherence of these trials to the Guidelines of the International Headache Society published in 2008.
Learn More >High expression of vascular endothelial growth factor (VEGF) is associated with immature angiogenesis within the urinary bladder wall and bladder afferent nerve sensitization leading to visceral hyperalgesia and pelvic pain. Research suggests a shift in VEGF alternative splice variant (VEGF-Aa, VEGF-Ab) expression with several pathologies (e.g., neuropathic pain and inflammation), as well as exhibiting differing effects on pain. Translational studies have also demonstrated increased total VEGF expression in the bladder of women with Interstitial cystitis/Bladder pain syndrome (IC/BPS). In this study, we quantified VEGF alternative splice variant expression in LUT tissues under control conditions and with CYP-induced cystitis. Using conscious cystometry, we further determined the functional effects of VEGFR2 receptor blockade on bladder function using intravesical instillation of a potent and selective VEGFR2 tyrosine kinase inhibitor (Ki8751, 1 mg/kg) in Wistar rats (male and female) with acute and chronic CYP-induced cystitis and controls (no CYP). With VEGFR2 receptor blockade, bladder capacity increased ( ≤ 0.01) in male and female control rats, as well as male and female rats with acute (p ≤ 0.05) or chronic (p ≤ 0.01, p ≤ 0.05 respectively) CYP-induced cystitis. Void volume also increased in female control (p ≤ 0.01) rats and female rats with acute (p ≤ 0.05) or chronic (p ≤ 0.05) CYP-induced cystitis, as well as in male control (p ≤ 0.05) rats and male rats with chronic (p ≤ 0.01) CYP-induced cystitis. These data suggest that VEGF may be a biomarker for IC/BPS and targeting VEGF/VEGFR2 signaling may be an effective treatment.
Learn More >Headache disorders are among the most common and disabling medical conditions worldwide. Pharmacologic acute and preventive treatments are often insufficient and poorly tolerated, and the majority of patients are unable to adhere to their migraine treatments due to these issues. With improvements in our understanding of migraine and cluster headache pathophysiology, neuromodulation devices have been developed as safe and effective acute and preventive treatment options. In this review, we focus on neuromodulation devices that have been studied for migraine and cluster headache, with special attention to those that have gained food and drug administration (FDA) clearance. We will also explore how these devices can be used in patients who might have limited pharmacologic options, including the elderly, children, and pregnant women.
Learn More >Inhibition of voltage-gated calcium (CaV) channels is a potential therapy for many neurological diseases including chronic pain. Neuronal CaV1/CaV2 channels are composed of α, β, γ and α2δ subunits. The β subunits of CaV channels are cytoplasmic proteins that increase the surface expression of the pore-forming α subunit of CaV. We targeted the high-affinity protein-protein interface of CaVβ's pocket within the CaVα subunit. Structure-based virtual screening of 50,000 small molecule library docked to the β subunit led to the identification of 2-(3,5-dimethylisoxazol-4-yl)-N-((4-((3-phenylpropyl)amino)quinazolin-2-yl)methyl)acetamide (IPPQ). This small molecule bound to CaVβ and inhibited its coupling with N-type voltage-gated calcium (CaV2.2) channels, leading to a reduction in CaV2.2 currents in rat dorsal root ganglion sensory neurons, decreased presynaptic localization of CaV2.2 in vivo, decreased frequency of spontaneous excitatory postsynaptic potentials and miniature excitatory postsynaptic potentials, and inhibited release of the nociceptive neurotransmitter calcitonin gene-related peptide from spinal cord. IPPQ did not target opioid receptors nor did it engage inhibitory G protein-coupled receptor signaling. IPPQ was antinociceptive in naive animals and reversed allodynia and hyperalgesia in models of acute (postsurgical) and neuropathic (spinal nerve ligation, chemotherapy- and gp120-induced peripheral neuropathy, and genome-edited neuropathy) pain. IPPQ did not cause akinesia or motor impairment, a common adverse effect of CaV2.2 targeting drugs, when injected into the brain. IPPQ, a quinazoline analog, represents a novel class of CaV2.2-targeting compounds that may serve as probes to interrogate CaVα-CaVβ function and ultimately be developed as a nonopioid therapeutic for chronic pain.
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