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Pain is evolutionarily hardwired to signal potential danger and threat. It has been proposed that altered pain-related associative learning processes, i.e., emotional or fear conditioning, might contribute to the development and maintenance of chronic pain. Pain in or near the face plays a special role in pain perception and processing, especially with regard to increased pain-related fear and unpleasantness. However, differences in pain-related learning mechanisms between the face and other body parts have not yet been investigated. Here, we examined body-site specific differences in associative emotional conditioning using electrical stimuli applied to the face and the hand. Acquisition, extinction, and reinstatement of cue-pain associations were assessed in a 2-day emotional conditioning paradigm using a within-subject design. Data of 34 healthy subjects revealed higher fear of face pain as compared to hand pain. During acquisition, face pain (as compared to hand pain) led to a steeper increase in pain-related negative emotions in response to conditioned stimuli (CS) as assessed using valence ratings. While no significant differences between both conditions were observed during the extinction phase, a reinstatement effect for face but not for hand pain was revealed on the descriptive level and contingency awareness was higher for face pain compared to hand pain. Our results indicate a stronger propensity to acquire cue-pain-associations for face compared to hand pain, which might also be reinstated more easily. These differences in learning and resultant pain-related emotions might play an important role in the chronification and high prevalence of chronic facial pain and stress the evolutionary significance of pain in the head and face.
Calcitonin gene related peptide (CGRP) monoclonal antibodies (mAbs) have been the first class of specifically developed preventive treatments for migraine. Clinical trials data suggest superiority of the CGRP mAbs to placebo in terms of prevention of migraine symptoms, migraine-specific quality of life and headache related disability. Treatment-related side effects overall did not differ significantly from placebo and discontinuation rate due to side effects has been low across the clinical trials, perhaps in view of their peripheral mode of action. Along with their route and frequency of administration, these novel class of drugs may constitute an improvement compared with the established arsenal of migraine treatments. Erenumab is a fully human antibody and the only mAb acting on the CGRP pathway by blocking its receptor. It is the first of the CGRP mAb class approved by the US Food and Drug Administration (May 2018) and the European Medicines Agency (July 2018). Erenumab exists in two different doses (70 mg and 140 mg) and it is administered with monthly subcutaneous injections. This review summarises erenumab pharmacological characteristics, clinical trials data, focusing on the potential role of this treatment in clinical practice.
Pain experience due to spinal degenerative disease decreases activity of daily living and quality of life. The present cross-sectional study was aimed at examining the sex-specific impact of pain severity, psychosocial factors, and insomnia on the disability due to chronic pain arising from spinal degenerative disease.
Cluster headache (CH) is considered to be a catastrophic disease presenting the most severe human pain condition. Available pharmacological treatments are hampered by unwanted side effects, and there is an urgent need for non-pharmacological treatment alternatives. We present a novel therapeutic approach for chronic CH, having evolved from an episodic CH, using a non-invasive percutaneous bioelectric current stimulation (PBCS), which generates static electric fields in the range of the naturally occurring electric potentials.
Initially developed to generate new treatments for epilepsy, gabapentin, and pregabalin ("gabapentinoids") were engineered to mimic the action of GABA and to modulate GABA metabolism. Rather than their intended pharmacological action on GABA neurotransmission, instead, they exhibit a high affinity for the α2δ-1 and α2δ-2 subunits of voltage-activated calcium channels, wherein binding of gabapentinoids inhibits cellular calcium influx and attenuates neurotransmission. Despite a lack of activity on GABA levels, gabapentin and pregabalin are effective at suppressing seizures and subsequently approved as a new class of antiepileptic therapy for partial-onset epilepsy. Through the same hypothesized molecular mechanism and by controlling neuronal hyperexcitability, gabapentinoids demonstrate clear efficacy in pain management, which has arguably been their most extensively prescribed application to date. In this review, we focus on pregabalin as a second-generation gabapentinoid widely employed in the treatment of a variety of pain conditions. We also discuss the wider functional roles of α2δ subunits and the contributions that pregabalin might play in affecting physiological and pathophysiological processes.
Cost utility analysis is important for measuring the impact of chronic disease and helps clinicians and policymakers in patient management and policy decisions, but generic preference-based measures are not always considered in clinical studies.
Neuropathic pain is characterized by sensory abnormalities, such as mechanical allodynia and heat hyperalgesia, associated with alteration in the peripheral and central nervous systems. After trigeminal nerve injury, phenotypic changes that involve the expression of calcitonin gene-related peptide occur in large- and medium-sized myelinated neurons; primary afferent neurons exhibit hyperexcitability because of neuron-glia interactions in the trigeminal ganglion. Increased nociceptive inputs from C- and Aδ-fiber and innocuous inputs from Aβ-fiber into the trigeminal spinal subnucleus caudalis (Vc) contribute to the phenotypic changes; further, they potentiate noxious information transmission in the ascending nociceptive pathways to the thalamus and parabrachial nucleus (PBN). It is noteworthy that C-fiber mediated nociceptive inputs can activate both the Vc-ventral posteromedial thalamic nucleus and Vc-PBN pathways, while mechanoreceptive fiber inputs specifically activate the Vc-PBN pathway. The Vc-PBN pathways project to the central nucleus of the amygdala (CeA) where affective behaviors are modulated. In addition, the PBN interacts with wakefulness-regulating neurons and hunger-sensitive neurons in the hypothalamus, suggesting that the Vc-PBN pathway can modulate sleep and appetite. Therefore, phenotypic changes in primary neurons and stimulus modality-specific activation of ascending nociceptive pathways to the PBN may exacerbate affective aspects of trigeminal neuropathic pain, including behavioral problems, such as sleep disturbance and anorexia, via the PBN-CeA-hypothalamus circuits.
Migraine is the most common acute primary headache in children and adolescents. In 2014, topiramate became the first preventive drug for migraine, approved by the Food and Drug Administration (FDA) for adolescents. This meta-analysis was aimed to evaluate the efficacy and safety of topiramate in the prevention of pediatric migraine. We searched the PubMed, EMBASE, Cochrane Library, and Chinese National Knowledge Infrastructure (CNKI) databases up to June 2019 for eligible randomized controlled trials (RCTs). The primary outcomes were mean migraine days per month, ≥50% reduction rate, and Pediatric Migraine Disability Assessment Scale (PedMIDAS) scores. RevMan5.3 software was performed for statistical analysis. Overall, 5 RCTs recruiting 531 patients (6-17 years of age) were included in the meta-analysis. The target dose of topiramate was 2 mg/kg (the maintenance phase was 12 weeks), 2-3 mg/kg, 50 mg/day, and 100 mg/day (maintaining for 16 weeks), respectively, in the included studies. Our results demonstrate that participants receiving topiramate had a significant advantage in remitting the monthly migraine days than those receiving placebo, with a mean difference (MD) of -0.78 ( = 531; 95% CI, -1.23 to -0.32; = 3.37; = 0.0008). Topiramate could also reduce the mean PedMIDAS scores ( = 238; 95% CI, -16.53 to -0.49; = 2.43; = 0.04). However, there was no significant difference in the percentage of patients experiencing a ≥50% reduction in monthly headache days between topiramate and placebo groups ( = 531; 95% CI, 0.94-1.77; = 1.58; = 0.11). Topiramate was associated with higher rates of side effects such as weight decrease ( = 395; 95% CI, 2.73-22.98; = 3.81; < 0.01) and paresthesia ( = 531; 95% CI, 3.05-13.18; = 4.94; < 0.01). Topiramate can significantly decrease monthly headache days and migraine-related burden in migraine patients <18 years old. However, it failed to increase 50% response rate. Adverse events seem to be more frequent in topiramate-treated children.
Pronounced activity-dependent slowing of conduction has been used to characterize mechano-insensitive, "silent" nociceptors and might be due to high expression of Na1.8 and could, therefore, be characterized by their tetrodotoxin-resistance (TTX-r). Nociceptor-class specific differences in action potential characteristics were studied by: (i) calcium imaging in single porcine nerve growth factor (NGF)-responsive neurites; (ii) extracellular recordings in functionally identified porcine silent nociceptors; and (iii) patch-clamp recordings from murine silent nociceptors, genetically defined by nicotinic acetylcholine receptor subunit alpha-3 (CHRNA3) expression. Porcine TTX-r neurites ( = 26) had more than twice as high calcium transients per action potential as compared to TTX-s neurites ( = 18). In pig skin, silent nociceptors ( = 14) characterized by pronounced activity-dependent slowing of conduction were found to be TTX-r, whereas polymodal nociceptors were TTX-s ( = 12) and had only moderate slowing. Mechano-insensitive cold nociceptors were also TTX-r but showed less activity-dependent slowing than polymodal nociceptors. Action potentials in murine silent nociceptors differed from putative polymodal nociceptors by longer duration and higher peak amplitudes. Longer duration AP in silent murine nociceptors linked to increased sodium load would be compatible with a pronounced activity-dependent slowing in pig silent nociceptors and longer AP durations could be in line with increased calcium transients per action potential observed in TTX-resistant NGF responsive porcine neurites. Even though there is no direct link between slowing and TTX-resistant channels, the results indicate that axons of silent nociceptors not only differ in their receptive but also in their axonal properties.
Chronic pelvic pain (CPP) in women is defined variably, but for clinical use it is cyclical or non-cyclical pain of at least 3-6 months' duration. It has major impacts on individuals and society. There are both structural and idiopathic causes. Whereas CPP is not curable in many cases, it is treatable. The most promising approach is multidisciplinary patient-centered care including cause-directed therapy, lifestyle changes, talking therapies, meditation, acupuncture, and physiotherapy (this is not a complete list). One of the most common structural causes for CPP is endometriosis. This review investigates current scientific concepts and recent innovations in this field as well as for CPP in general.