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Although topical drugs are the mainstay of treatment for patients with mild-to-moderate psoriasis, the developments observed in this field in the last two decades have been limited. The most commonly used drugs are still vitamin D analogues and corticosteroids, both with several limitations. The aryl hydrocarbon receptor (AhR) plays a role in the pathogenesis of psoriasis, and tapinarof, a novel, first-in-class, small molecule topical therapeutic AhR-modulating agent has been recently approved by the FDA for the topical treatment of plaque psoriasis in adults. Two large, 12-week, phase III trials, PSOARING 1 and 2, showed that 35.4-40.2% of patients in the tapinarof 1% cream arm achieved the primary endpoint (Physician's Global Assessment (PGA) score of 0 or 1 and a decrease of ≥ 2-5 points at week 12) compared with 6.0-6.3% for vehicle arm, respectively. The most common adverse effects were folliculitis, contact dermatitis, headache and pruritus. In the open label, 40-week, extension trial, PSOARING 3, the efficacy and safety results were similar, with 40.9% of patients achieving a PGA=0 at least one time during the trial and 58.2% of patients with PGA≥2 achieved PGA=0/1 at least once during the trial, without tachyphylaxis. There were no new safety signals, with most frequent adverse events being folliculitis, contact dermatitis, and upper respiratory tract infection. Tapinarof 1% cream has shown to be effective and to have a favourable safety profile in the treatment of psoriatic patients, representing an alternative to the current therapeutic options, increasing our armamentarium in the topical treatment of psoriasis. This article is protected by copyright. All rights reserved.
Learn More >Existing data demonstrate reduced delta power during sleep in patients with depression and chronic pain. However, there has been little examination of the relationship between delta power and pain-reports, or pain-catastrophizing. We recruited female participants (n=111) with insomnia and temporomandibular disorder, and measured nocturnal and daytime measures of pain and pain catastrophizing, and calculated relative nocturnal delta (0.5-4 Hz) power during sleep. We fit linear regression models, and further examined the moderating effect of depressive symptom severity. Lower relative delta power across the whole night was significantly associated with greater nocturnal pain (B = -20.276, p = 0.025, R = 0.214). Lower relative delta power during the first-third of the night, was associated with greater nocturnal pain (B = -17.807, p = 0.019, R = 0.217), next-day pain (B = 13.876, p = 0.039, R = 0.195), and next-morning pain (B = -15.751, p = 0.022, R = 0.198). Lower relative delta power during the final-third of the night was significantly associated with greater nocturnal (B = -17.602, p = 0.029, R = 0.207) and next-morning pain (3: B = -14.943, p = 0.042, R = 0.187). Depressive symptom severity did not moderate these relationships. Delta power was not significantly associated with nocturnal or daytime pain catastrophizing. These findings demonstrate that greater relative delta power during sleep is associated with lower nocturnal and next-day pain in patients with temporomandibular disorder. This data may guide the use of sleep interventions in clinical pain populations, with the aim of improving pain outcomes. PERSPECTIVE: This article presents data demonstrating an association between increased nocturnal delta power and reduced next-day pain. These findings may help promote interventions which aim to increase nocturnal delta power in clinical pain populations, with the goal of improving pain outcomes.
Learn More >Treatment wearing-off has been reported for calcitonin gene-related peptide-pathway monoclonal antibodies, including erenumab, specifically in the last week of the monthly dosing cycle.
Learn More >Tension type headache (TTH) is a prevalent but poorly understood pain disease. Current understanding supports the presence of multiple associations underlying its pathogenesis. Our aim was to compare competing multivariate pathway models that explains the complexity of TTH. Headache features (intensity, frequency, or duration – headache diary), headache-related disability (Headache Disability Inventory-HDI), anxiety/depression (Hospital Anxiety and Depression Scale), sleep quality (Pittsburgh Sleep Quality Index), widespread pressure pain thresholds (PPTs) and trigger points (TrPs) were collected in 208 individuals with TTH. Four latent variables were formed from the observed variables – Distress (anxiety, depression), Disability (HDI subscales), Severity (headache features), and Sensitivity (all PPTs). Structural equation modelling (SEM) and Bayesian network (BN) analyses were used to build and compare a theoretical (model) and a data-driven (model) latent variable model. The model (root mean square error of approximation [RMSEA] = 0.035) provided a better statistical fit than model (RMSEA = 0.094). The only path common between model and model was the influence of years with pain on TrPs. The model revealed that the largest coefficient magnitudes were between the latent variables of Distress and Disability (β=1.524, P=0.006). Our theoretical model proposes a relationship whereby psycho-physical and psychological factors result in clinical features of headache and ultimately affect disability. Our data-driven model proposes a more complex relationship where poor sleep, psychological factors, and the number of years with pain takes more relevance at influencing disability. Our data-driven model could be leveraged in clinical trials investigating treatment approaches in TTH.
Learn More >Methylmercury (MeHg), an environmental toxicant, is known to cause sensory impairment by inducing neurodegeneration of sensory nervous systems. However, in recent years, it has been revealed that neuropathic pain occurs in the chronic phase of MeHg poisoning, that is, in current Minamata disease patients. Our recent study using Minamata disease model rats demonstrated that MeHg-mediated neurodegeneration in the sensory nervous system may induce inflammatory microglia production in the dorsal horn of the spinal cord and subsequent somatosensory cortical rewiring, leading to neuropathic pain. We hypothesized that inhibition of the Rho-associated coiled coil-forming protein kinase (ROCK) pathway could prevent MeHg-induced neuropathic pain because the ROCK pathway is known to be involved in inducing the production of inflammatory microglia. Here, we showed for the first time that Fasudil, a ROCK inhibitor, can prevent neuropathic pain in Minamata disease model rats. In this model, Fasudil significantly suppressed nerve injury-induced inflammatory microglia production in the dorsal horn of the spinal cord and prevented subsequent somatosensory cortical rewiring. These results suggest that the ROCK pathway is involved in the onset and development of neuropathic pain in the chronic phase of Minamata disease, and that its inhibition is effective in pain prevention.
Learn More >To summarize the pharmacology of the calcitonin peptide family of receptors and explore their relationship to migraine and current migraine therapies.
Learn More >Investigations of migraine among childhood cancer survivors have predominantly relied on self-reported information and hospital discharge diagnoses. Alone, both approaches are liable to bias. We used Danish nationwide registers to obtain data on both prescriptions of acute migraine medications (antimigraines) and hospital discharge diagnoses of migraine to assess the relative risk of migraine across a wider spectrum of migraine presentations than previously studied.
Learn More >Eliminating unnecessary pain is an important requirement of performing animal experimentation, including reducing and controlling pain of animals used in pain research. The goal of this study was to refine an adjuvant-induced monoarthritis model in rats by providing analgesia with a transdermal fentanyl solution (TFS). Male and female Sprague-Dawley rats, single- or pair-housed, were injected with 20 μL of complete Freund adjuvant (CFA) into the left ankle joint. CFA-injected rats treated with a single dose of transdermal fentanyl solution (0.33 or 1 mg/kg) were compared with an untreated CFA-injected group and sham groups that received either no treatment or TFS treatment (1 mg/kg) during 72 h. At the tested doses, TFS reduced mechanical hyperalgesia and improved the mobility, stance, rearing, and lameness scores at 6 h after CFA injection. Joint circumferences were not reduced by TFS treatment, and no significant differences were detected between the 2 doses of TFS, or between single- and pair-housed rats. Treatment with TFS did not appear to interfere with model development and characteristics. However, overall, the analgesic effect was transient, and several opioid-related side effects were observed.
Learn More >Distinct roles of dopamine receptor subtypes in the nucleus accumbens during itch signal processing.
Ventral tegmental area (VTA) dopaminergic neurons, which are well known for their central roles in reward and motivation-related behaviors, have been shown to participate in itch processing via their projection to the nucleus accumbens (NAc). However, the functional roles of different dopamine receptor subtypes in subregions of the NAc during itch processing remain unknown. With pharmacological approaches, we found that the blockade of dopamine D1 receptors (D1R), but not dopamine D2 receptors (D2R), in the lateral shell (LaSh) of the NAc impaired pruritogen-induced scratching behavior in male mice. In contrast, pharmacological activation of D2R in both the LaSh and medial shell (MeSh) of the NAc attenuated the scratching behavior induced by pruritogens. Consistently, we found that dopamine release, as detected by a dopamine sensor, was elevated in the LaSh rather than the MeSh of the NAc at the onset of scratching behavior. Furthermore, the elevation of dopamine release in the LaSh of the NAc persisted even though itch-relieving behavior was blocked, suggesting that the dopamine signal in the NAc LaSh represents a motivational component of itch processing. Our study revealed different dynamics of dopamine release that target neurons expressing different dopamine receptors within different subregions of the NAc, and emphasized that D1R in the LaSh of the NAc is important in itch signal processing.Dopamine has been implicated in itch signal processing. However, the mechanism underlying the functional role of dopamine in itch processing remains largely unknown. Here, we examined the role of D1R and D2R in the NAc shell during pruritogen-induced scratching behavior. We demonstrated that D1R in the NAc LaSh might play an important role in motivating itch-induced scratching behavior, while activation of D2R would terminate scratching behavior. Our study revealed the diverse functional roles of dopamine signals in the NAc shell during itch processing.
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