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Prescribers are often confronted with the decision to escalate opioid doses to achieve adequate analgesia. Understanding the impact of dose escalation on pain intensity is warranted. Using a retrospective cohort study design, Veterans with chronic pain and chronic opioid therapy were identified. Opioid dose escalators (>20% increase in average morphine milligram equivalent [MME] daily dose) were compared to dose maintainers (±20% change in average MME daily dose) assessed over two consecutive 6 month windows. Pain intensity was measured by the Numeric Rating Scale (NRS). The primary analyses used linear repeated measures models among a 1:1 matched sample of escalators and maintainers matched on propensity score and within ±180 days of the index date. Sensitivity analyses were conducted using adjusted linear repeated measures models with and without incorporating stabilized inverse probability of treatment weighting (SIPTW). There were 32,420 dose maintainers and 20,767 dose escalators identified with 19,358 (93%) matched pairs. Pain scores were persistently higher among dose escalators at each 90 day time period after the index date (0-90 Days After Index Date: Dose Escalators:4.68, 95%CI: 4.64, 4.72 Dose Maintainers:4.32, 95%CI: 4.28, 4.36, p<0.0001; 91-180 Days After Index Date: Dose Escalators:4.53, 95%CI: 4.49, 4.57; Dose Maintainers:4.25, 95%CI: 4.22, 4.29, p<0.0001) but were not different in the 90 days prior to the index date (Dose Escalators:4.64, 95%CI: 4.61, 4.68; Dose Maintainers:4.59, 95%CI: 4.55, 4.63, p=0.0551). Sensitivity analyses provided similar results as the primary analyses. Opioid dose escalation among patients with chronic pain is not associated with improvements in NRS pain scores.
Learn More >To evaluate the long-term safety and tolerability of ubrogepant for the acute treatment of migraine.
Learn More >The efficacy and safety of high-dose intravenous immunoglobulin (IVIG) in treatment-resistant diabetic painful polyneuropathy (DPN) were assessed.
Learn More >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 >The aim of this systematic review was to summarize the effects of physical exercise on neuropathic pain (NP) in animal models of SCI. The search was conducted in Medline and Science Direct to identify experimental pre-clinical studies involving animal models of SCI, physical exercise as an intervention and the assessment of NP. Fifteen articles met the eligibility criteria. The review shows that in studies of NP involving animal models of SCI, rodents are the most common species. Thoracic contusion is the most common injury and mechanical and thermal nociception are the most frequently assessed NP components. The benefits of physical exercise vary according to its starting period and total duration. In addition, there is considerable heterogeneity regarding the type and intensity of exercise capable of alleviating NP after SCI. Furthermore, physical exercise has beneficial effects on mechanical, thermal and cold nociception, and spontaneous pain. These results are weakened by the paucity of studies involving these pain outcomes. The review protocol is published for free access on the SyRF platform (http://syrf.org.uk/protocols/).
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.
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