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There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.
Learn More >Here we show, for the first time, spontaneous cortical spreading depolarization (CSD) events – the electrophysiological correlate of the migraine aura – in animals by using the first generated familial hemiplegic migraine type 3 (FHM3) transgenic mouse model. The mutant mice express L263V-mutated α1 subunits in voltage-gated Na 1.1 sodium channels (Scn1a ). CSDs consistently propagated from visual to motor cortex, recapitulating what has been shown in patients with migraine with aura. This model may be valuable for the preclinical study of migraine with aura and other diseases in which spreading depolarization is a prominent feature.
Learn More >SAR studies of a reported menthol-based TRPM8 antagonist, guided by computational simulations and structure-based design, uncovers a novel series of TRPM8 antagonists with >10-fold selectivity versus related TRP subtypes. Spiro[4.5]decan-8-yl analog 14 inhibits icilin-evoked Ca2+ entry in HEK-293 cells stably expressing human TRPM8 (hTRPM8) with an IC50: 2.4 ± 1.0 nM, while in whole-cell patch-clamp recordings, this analog inhibits menthol-evoked currents with an hTRPM8 IC50: 64 ± 2 nM. Molecular dynamics (MD) simulations of compound 14 in our homology model of hTRPM8 suggests that this antagonist forms extensive hydrophobic contacts within the orthosteric site. In the wet dog shakes (WDS) assay, compound 14 dose-dependently blocks icilin-triggered shaking behaviors in mice. Upon local administration, compound 14 dose dependently inhibits cold allodynia evoked by the chemotherapy oxaliplatin in a murine model of peripheral neuropathy at microgram doses. Our findings suggest that 14 and other biphenyl amide analogs within our series can find utility as potent antagonist chemical probes derived from (-)-menthol, as well as small molecule therapeutic scaffolds for chemotherapy-induced peripheral neuropathy (CIPN) and other sensory neuropathies.
Learn More >In health and disease, the somatosensory system has been interrogated with standardized research techniques, collectively referred to as quantitative sensory testing (QST). In neuropathic pain, QST has been used to characterize multiple sensory derangements. However, the use of QST outside the lab has been limited by several factors, including a lack of standardization, variability in procedural technique, and duration of testing that would be unacceptable for clinic. To address these shortcomings, the Neuropathic Pain Research Consortium (NPRC) designed an easy and low-cost "bedside" QST procedure. To test the hypothesis that this procedure would be clinically reliable over time and across different examiners, a multi-site, blinded study was performed in subjects with postherpetic neuralgia. Generally, agreement between two examiners and over two study visits with one examiner was high. Additionally, intraclass correlation coefficients and Kappa statistics calculated showed that the battery of QST tests included were highly reliable. Interestingly, mechanical modalities (light brush, pinprick, pressure, and vibration) showed the highest reliability. The least reliable modalities were cool (room temperature) and warmth (38°C). These data demonstrate that the NPRC beside QST protocol is reliable across examiner and over time, providing a validated QST tool for use in clinical practice and clinical trials. Perspective: This blinded, multi-center trial in 32 patients with postherpetic neuralgia demonstrates bedside quantitative sensory testing is reliable and suitable as a clinical trial outcome. The novel bedside battery could be used in clinical trials or in clinical practice over time given the reliability data presented in this article.
Learn More >Many individuals with chronic musculoskeletal pain (CMP) show impairments in their pain-modulatory capacity. Although stress plays an important role in chronic pain, it is not known if stress-induced analgesia (SIA) is affected in patients with CMP. We investigated SIA in 22 patients with CMP and 18 pain-free participants. Pain thresholds, pain tolerance and suprathreshold pain ratings were examined before and after a cognitive stressor that typically induces pain reduction (SIA). Whereas the controls displayed a significant increase in pain threshold in response to the stressor, the patients with CMP showed no analgesia. In addition, increased pain intensity ratings after the stressor indicated hyperalgesia (SIH) in the patients with CMP compared to controls. An exploratory analysis showed no significant association of SIA or SIH with spatial pain extent. We did not observe significant changes in pain tolerance or pain unpleasantness ratings after the stressor in patients with CMP or controls. Our data suggest that altered stress-induced pain modulation is an important mechanism involved in CMP. Future studies need to clarify the psychobiological mechanisms of these stress-induced alterations in pain processing and determine the role of contributing factors such as early childhood trauma, catastrophizing, comorbidity with mental disorders and genetic predisposition.
Learn More >measures such as disability-adjusted life years (DALY) are becoming increasingly important for the standardized assessment of the burden of disease due to death and disability. The BURDEN 2020 pilot project was designed as an independent burden-ofdisease study for Germany, which was based on nationwide data, but which also yielded regional estimates.
Learn More >The physicochemical stimulation of acupoints is a widespread treatment strategy for different diseases, such as sciatica. Its efficacy is mainly based on the temporal and spatial modulation of the physicochemical properties of the acupoints. The existing therapies based on the stimulation of acupoints have certain disadvantages. Therefore, in this study, injectable dexamethasone (DXM)- and magnetic FeO nanoparticles-loaded chitosan/β-glycerophosphate (CS/GP) thermal crosslinking hydrogels were prepared, thereby improving the performance of embedding materials. The sciatica rat models were established to compare the therapeutic effects of hydrogels and catgut. The DXM or FeO-loaded CS/GP hydrogels were compared in terms of their gelation kinetics, release kinetics, magnetic responsiveness , and biocompatibility as well as their analgesic effects on the chronic constriction injury of the sciatic nerve (CCI) rats . The CS/GP/FeO/DXM hydrogel showed comparable gelation kinetics and good magnetic responsiveness . This hydrogel could relieve sciatica by reducing the expression levels of inflammatory factors in serum, inhibiting the p38MAPK (p38, mitogen-activated protein kinase) phosphorylation, and decreasing the expression level of the P2X4 receptor (P2X4R) in the spinal dorsal horn. In conclusion, the DXM or FeO-loaded CS/GP hydrogels can be considered as a treatment option for the physiochemical stimulation therapy of acupoints to improve sciatica.
Learn More >Despite the rising availability and use of medical marijuana (MM) in the USA, little is known about the demographics, clinical characteristics, or quality of life of MM patients. This study describes the demographic characteristics and health-related quality of life (HRQoL) of MM patients who are initiating treatment in Pennsylvania.
Learn More >Central sensitization (CS) involves dysfunctional central nervous system pain modulation resulting in heightened pain perception. Central sensitization is not commonly assessed among patients with opioid use disorder (OUD), despite the fact that pain has been implicated in the development, maintenance, and relapse of OUD and chronic opioid use may produce opioid-induced hyperalgesia. Central sensitization is a plausibly important mechanism underlying the complex relationship between OUD and chronic pain. However, this premise is largely untested.
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