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Sustained Efficacy, Safety and High Adherence Rate of Onabotulinum Toxin Type A in Chronic Migraine Patients: A Multicentric Prospective Real-Life Study.

Guidelines regarding long-term use with onabotulinumtoxinA (onaBT-A) in chronic migraine (CM) prophylaxis are lacking. This multicentric prospective real-life study aimed to assess the efficacy and safety of a long-term treatment. A total of 195 chronic migraine patients were treated with onaBT-A, every 3 months for 5 cycles (Phase 1). In the Phase 2 of the study, depending on response rate, patients were divided into "responders" (R), "partially responders" (PR) and "non-responders" (NR). Then, we proposed to R and PR patients to continue with an additional 12 months of treatment (additional 4 sessions). Response to treatment and adverse events were collected for the entire duration of the study. Of the 195 patients included (females 82.1%, mean age 47.4 ± 12.4), at the end of Phase 1 there were 52.3% of R patients, 17.9% of PR patients, 15.4% of NR patients and 14.4% drop-outs. During Phase 2 of treatment, R patients presented a maintenance of the improvement achieved during the first year of treatment, as well as PR patients. Except for three serious adverse events not related to treatment, all other adverse events were mild or moderate in severity and resolved without sequelae. In the literature, adherence to oral migraine-preventive medications among patients with CM was found to be less than 25%. The results of this prospective real-life multicenter study show efficacy, safety and adherence to a long-term treatment with onaBT-A.

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TRP Channels: Recent Development in Translational Research and Potential Therapeutic Targets in Migraine.

Migraine is a chronic neurological disorder that affects approximately 12% of the population. The cause of migraine headaches is not yet known, however, when the trigeminal system is activated, neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) are released, which cause neurogenic inflammation and sensitization. Advances in the understanding of migraine pathophysiology have identified new potential pharmacological targets. In recent years, transient receptor potential (TRP) channels have been the focus of attention in the pathophysiology of various pain disorders, including primary headaches. Genetic and pharmacological data suggest the role of TRP channels in pain sensation and the activation and sensitization of dural afferents. In addition, TRP channels are widely expressed in the trigeminal system and brain regions which are associated with the pathophysiology of migraine and furthermore, co-localize several neuropeptides that are implicated in the development of migraine attacks. Moreover, there are several migraine trigger agents known to activate TRP channels. Based on these, TRP channels have an essential role in migraine pain and associated symptoms, such as hyperalgesia and allodynia. In this review, we discuss the role of the certain TRP channels in migraine pathophysiology and their therapeutic applicability.

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AQP4 mitigates chronic neuropathic pain-induced cognitive impairment in mice.

Neuropathic pain is a risk factor for cognitive defects. The ubiquitous expression of AQP4 in astrocytes throughout the central nervous system is altered in the neurodegenerative disease. However, the exact role of AQP4 in cognitive impairment induced by chronic neuropathic pain remains unclear. In this study, we discovered that AQP4 protein and mRNA expression decreased time-dependently in the model of chronic neuropathic pain-induced cognitive disorder. AQP4 overexpression recovered mice from cognitive impairment. Furthermore, the concentration of Aβ1-42 in the serum and hippocampus reduced in mice with AQP4 overexpression adeno-associated virus injection. In conclusion, AQP4 in astrocytes is important in mitigating cognitive impairment caused by chronic neuropathic pain.

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Describing the Non-Surgical, Non-Pharmacological Interventions Offered to Adolescents with Persistent Back Pain in Randomized Trials: A Scoping Review.

Persistent non-specific back pain is now established as a biopsychosocial phenomenon that can be meaningfully affected by individuals' cognitions, emotions, lifestyle factors, and family and social relationships. Recent guidelines for the treatment of adolescents with persistent non-specific back pain, as well as those for youth with mixed chronic pain, strongly recommend interdisciplinary care in which adolescents receive treatment for both mind and body. The objective of this scoping review was to examine the interventions evaluated in randomized trials for adolescents with persistent back pain to determine if they correspond to these guidelines and to reveal future research priorities.

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Polymorphisms of the Proinflammatory Cytokine Genes Modulate the Response to NSAIDs but Not to Triptans in Migraine Attacks.

Migraine is a common neurovascular disorder characterized by recurrent episodes of headache and associated neurological symptoms. At present, a significant portion of patients do not obtain a satisfactory response to acute pain-relieving therapies, including NSAIDs and triptans. In this context, pharmacogenetics plays a key role in the understanding of such a diverse response. In order to investigate whether functional polymorphisms in proinflammatory cytokine genes (, , ; and ) may influence the response to acute treatment, 313 consecutive patients with episodic migraine without aura were enrolled. Pain relief by administration of NSAIDs or triptans for three consecutive migraine attacks was evaluated. We found a significant association between A allele of the promoter (-308 A/G) and a lack of efficacy after NSAID administration ( < 0.01, OR 2.51, 95% CI: 1.33 < OR < 4.75 compared to the G allele). Remaining polymorphisms had no significant effect on pain relief. Our study showed that a functional polymorphism in the gene significantly modulates the clinical response to NSAID administration in acute attacks. Patients with higher production of the active cytokine during stress showed a significantly lower anti-migraine effect. Our results further support a role for TNF-α in the pathophysiological mechanisms of migraine attack.

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Analgesic Action of Acetaminophen via Kv7 Channels.

The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 channel blocker XE991 on APAP-induced analgesia was investigated in vivo. APAP had no effect on naive animals. Induction of inflammation with λ-carrageenan lowered mechanical and thermal thresholds. Systemic treatment with APAP reduced mechanical hyperalgesia, and co-application of XE991 reduced APAP's analgesic effect on mechanical pain. In a second experiment, the analgesic effect of systemic APAP was not antagonized by intrathecal XE991 application. Analysis of liver samples revealed APAP and glutathione-coupled APAP indicative of metabolization. However, there were no relevant levels of these metabolites in cerebrospinal fluid, suggesting no relevant APAP metabolite formation in the CNS. In summary, the results support an analgesic action of APAP by activating Kv7 channels at a peripheral site through formation of the metabolite NAPQI.

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Preclinical Studies of Posttraumatic Headache and the Potential Therapeutics.

Posttraumatic headache (PTH) attributed to traumatic brain injury (TBI) is a secondary headache developed within 7 days after head injury, and in a substantial number of patients PTH becomes chronic and lasts for more than 3 months. Current medications are almost entirely relied on the treatment of primary headache such as migraine, due to its migraine-like phenotype and the limited understanding on the PTH pathogenic mechanisms. To this end, increasing preclinical studies have been conducted in the last decade. We focus in this review on the trigeminovascular system from the animal studies since it provides the primary nociceptive sensory afferents innervating the head and face region, and the pathological changes in the trigeminal pathway are thought to play a key role in the development of PTH. In addition to the pathologies, PTH-like behaviors induced by TBI and further exacerbated by nitroglycerin, a general headache inducer through vasodilation are reviewed. We will overview the current pharmacotherapies including calcitonin gene-related peptide (CGRP) monoclonal antibody and sumatriptan in the PTH animal models. Given that modulation of the endocannabinoid (eCB) system has been well-documented in the treatment of migraine and TBI, the therapeutic potential of eCB in PTH will also be discussed.

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Patients with Functional Somatic Syndromes–Fibromyalgia, Irritable Bowel Syndrome, Chronic Headaches, and Chronic Low Back Pain–Have Lower Outcomes And Higher Opioid Usage And Cost After Shoulder And Elbow Surgery.

To perform a systematic review assessing the relationship between functional somatic syndromes (FSSs) and patient-reported outcome measures (PROMs), post-operative opioid consumption, and hospitalization costs after shoulder and elbow surgery.

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Clinical assessment of mechanical allodynia in youth with complex regional pain syndrome: Development and preliminary validation of the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense).

Youth with complex regional pain syndrome (CRPS) commonly experience mechanical allodynia and disability. Assessment of mechanical allodynia is typically binary (present or absent), making it difficult to assess the quality and degree of mechanical allodynia before and after treatment. This study developed and validated the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) to provide an easy way for rehabilitation clinicians to evaluate mechanical allodynia before and after intensive interdisciplinary pain treatment. The six Pedi-Sense items demonstrated adequate internal consistency reliability (CR) at admission (CR = 0.956) and discharge (CR = 0.973), reasonably fit the hypothesized linear model of stimulus intensity (p<0.0001), and significantly loaded onto a single latent factor, mechanical allodynia (p<0.0001), at admission and discharge. Pedi-Sense scores significantly correlated with disability (r = 0.40; p = 0.004) and pain catastrophizing (r = 0.33; p = 0.017) at admission. The Pedi-Sense appeared responsive to intervention as participants' total scores improved by 1.44 points (95% CI: 0.72, 2.15) after IIPT interventions that included daily tactile desensitization. However, test-retest and interrater reliability and the specific contribution of desensitization treatment to the overall success of multi-modal pain rehabilitation still needs to be evaluated. PERSPECTIVE: This article presents the development and preliminary validation of a novel clinical assessment of static and dynamic mechanical allodynia. The Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) allows rehabilitation clinicians to easily evaluate mechanical allodynia at the bedside with minimal training and simple equipment to guide desensitization treatment in clinical settings.

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Sex differences in patient journeys to diagnosis, referral, and surgical treatment of trigeminal neuralgia: implications for equitable care.

Trigeminal neuralgia (TN) is an orofacial pain disorder that is more prevalent in females than males. Although an increasing number of studies point to sex differences in chronic pain, how sex impacts TN patients' journeys to care has not been previously addressed. This study sought to investigate sex differences in patients' journeys to diagnosis, referral, and treatment of TN within a large national context.

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