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The prevalence of neuropathic pain is estimated to be between 7 and 10% in the general population. The efficacy of intravenous (IV) lidocaine has been studied by numerous clinical trials on patients with neuropathic pain. The aim of this systematic review and meta-analysis was to evaluate the efficacy of IV lidocaine compared with a placebo for neuropathic pain and secondly to assess the safety of its administration. A literature search on PubMed, Scopus, CENTRAL (Cochrane Central Register of Controlled Trials), and Google scholar databases was performed for relevant studies published up to February 2019. Randomized controlled trials (RCTs) evaluating IV lidocaine treatment for pain relief in patients with neuropathic pain were included. 26 articles met the inclusion criteria. Patients with varied etiology of neuropathic pain were among the patient samples of these studies. Fifteen articles were included for quantitative analysis. Lidocaine was superior to a placebo in relieving neuropathic pain in the early post-infusion period [Mean Difference (MD) = -11.9; 95% Confidence interval (CI): -16.8 to -7; < 0.00001]. Multiple infusions of lidocaine over a period of 4 weeks, however, had no significant effect on reliving neuropathic pain (MD = -0.96; 95% CI: -2.02 to 0.11; = 0.08). IV lidocaine was also associated with a significant number of adverse events compared to a placebo [Odds Ratio (OR) = 7.75; 95% CI: 3.18-18.92; < 0.00001]. Our study indicates that while IV lidocaine is effective in pain control among patients with neuropathic pain in the immediate post-infusion period, it does not have a long-lasting, persistent effect. IV infusions of the drug are associated with an increased risk of side effects compared to a placebo. However, the risk of serious adverse events is negligible. Further, well-designed RCTs evaluating the effects of various dosages and infusion periods of IV lidocaine are required to provide clear guidelines on its clinical use.
Learn More >Voltage-gated calcium channels (VGCCs) are important mediators of pain hypersensitivity during inflammatory states, but their role in sensory nerve growth remains underexplored. Here, we assess the role of the N-type calcium channel Cav2.2 in the complete Freund's adjuvant (CFA) model of inflammatory pain. We demonstrate with hybridization and immunoblotting, an increase in Cav2.2 expression after hind paw CFA injection in sensory neurons that respond to thermal stimuli, but not in two different mechanosensitive neuronal populations. Further, Cav2.2 upregulation post-CFA correlates with thermal but not mechanical hyperalgesia in behaving mice, and this hypersensitivity is blocked with a specific Cav2.2 inhibitor. Voltage clamp recordings reveal a significant increase in Cav2.2 currents post-CFA, while current clamp analyses demonstrate a significant increase in action potential frequency. Moreover, CFA-induced sensory nerve growth, which involves the extracellular signal-related kinase (ERK1/2) signaling pathway and likely contributes to inflammation-induced hyperalgesia, was blocked with the Cav2.2 inhibitor. Together, this work uncovers a role for Cav2.2 during inflammation, demonstrating that VGCC activity can promote thermal hyperalgesia through both changes in firing rates of sensory neurons as well as promotion of new neurite outgrowth.
Learn More >The sensitizing effect of capsaicin has been previously characterized using laser and contact heat evoked potentials (LEPs and CHEPs) by stimulating in the primary area of hyperalgesia. Interestingly, only CHEPs reveal changes consistent with notion of peripheral sensitization (i.e., reduced latencies). The aim of this study was to investigate contact heat stimulation parameters necessary to detect peripheral sensitization related to the topical application of capsaicin, and therefore significantly improve the current method of measuring peripheral sensitization via CHEPs. Rapid contact heat stimulation (70°C/s) was applied from three different baseline temperatures (35, 38.5, and 42°C) to a 52°C peak temperature, before and after the topical application of capsaicin on the hand dorsum. Increased pain ratings in the primary area of hyperalgesia were accompanied by reduced N2 latency. Changes in N2 latency were, however, only significant following stimulation from 35 and 38.5°C baseline temperatures. These findings suggest that earlier recruitment of capsaicin-sensitized afferents occurs between 35 and 42°C, as stimulations from 42°C baseline were unchanged by capsaicin. This is in line with reduced thresholds of type II A-delta mechanoheat (AMH) nociceptors following sensitization. Conventional CHEP stimulation, with a baseline temperature below 42°C, is well suited to objectively detect evidence of peripheral sensitization.
Learn More >Everyday variations in night sleep in healthy pain-free subjects are at most weakly associated with pain, whereas strong alterations (eg, sleep deprivation, insomnia) lead to hyperalgesic pain changes. Since it remains unclear how substantial sleep alterations need to be in order to affect the pain system and lead to a coupling of both functions, the present study aimed at providing sufficient variance for co-variance analyses by examining a sample consisting of both healthy subjects and chronic pain patients.
Learn More >Few studies have been conducted on the prodromal and postdromal phases of the migraine attack in children and adolescents. Using a questionnaire, we found that 67% of 103 children and adolescents with migraine reported at least one prodromal symptom, with a mean number per subject of 1.8 (median 2.2). The most frequently reported prodromal symptoms were face changes, fatigue and irritability. In pediatric patients selected as having prodrome, fatigue, mood change and neck stiffness were the most frequently reported prodromal symptoms. Using a different design, Laurell et al. found that 71% of 137 pediatric patients reported at least one prodromal symptom with a mean number per subject of 1.9 ± 2.0. Studying postdrome was fraught with unexpected difficulties as our preliminary research showed. Patients reported 2 groups of symptoms occurring during the resolution phase of the headache: symptoms whose onset was headache cessation and were persisting it, and symptoms whose onset was headache cessation. We referred to the former as persistent symptoms and to the latter as true postdromes. Ninety-one per cent of patients reported persistent symptoms, with a mean of 6.0 and a median of 2, asthenia, pallor, cognitive difficulties, anorexia, somnolence, and nausea being the more frequently reported. True postdromes were reported by 82% of patients, with a mean of 2.6 and a median of 2, thirst, somnolence, visual disturbances, food craving, paraesthesias, and ocular pain being the most frequent reported. Interestingly, several prodromal and postdromal symptoms are also encountered during the aura classic and/or accompany the headache phase. Functional imaging in migraine has showed that the activations in areas such as hypothalamus or brainstem may begin before headache onset and/or persist after headache relief. Thus, one may wonder whether prodromal and postdromal symptoms may indicate the involvement of the limbic system, dopaminergic pathways, the hypothalamus and the brainstem. Differences between children, adolescents and adults might contribute to the understanding of migraine neurobiology.
Learn More >Increasing knowledge about the role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology has led to the development of antibodies against this peptide or its receptor. However, CGRP is widely expressed throughout the body, participating not only in pathophysiological conditions but also in several physiological processes and homeostatic responses during pathophysiological events. Therefore, in this chapter, the risks of long-term blockade of the CGRP pathway will be discussed, with focus on the cardiovascular system, as this peptide has been described to have a protective role during ischemic events, and migraine patients present a higher risk of stroke and myocardial infarction.
Learn More >Pain in sickle cell disease (SCD) is severe, variable, and inadequately comprehended. The β2-adrenergic receptor () is critical in mediating neurotransmitter response in the sympathetic nervous system. In this association study, we examined 16 single nucleotide polymorphisms (SNPs) covering 5'-UTR and coding regions of for pain variability in SCD. Subjects recorded their non-crisis, baseline pain experience on a computerized tool from which we obtained chronic pain measurement score- composite pain index (CPI). Regression models yielded significant associations between chronic pain and seven SNPs. Non-synonymous SNP rs1042713 A allele (Arg16) caused a 5.73-fold decrease in CPI ( = 0.002). Allele A of rs12654778 and T of rs17778257 reduced CPI by a fold of 4.52 ( = 0.019), and 4.39 ( = 0.032), respectively. Whereas, in the 5' UTR, allele C of rs1042711, G of rs11168070, C of rs11959427, and C of rs1801704 increased CPI by a fold of 10.86 ( = 0.00049), 5.99 ( = 0.016), 5.69 ( = 0.023), and 5.26 ( = 0.031), respectively. Together, these SNPs accounted for 2-15% of CPI variance after adjusting for covariates. Moreover, these SNPs were in high linkage disequilibrium (LD) showing three LD blocks in our cohort. A 10-marker haplotype increased CPI by 11.5-fold ( = 0.000407). Thus, polymorphisms might contribute to chronic pain severity and heterogeneity in SCD.
Learn More >Kappa receptor activation by dynorphins contributes to the anxiogenic, dysphoric, and cognitive disrupting effects of repeated stress, suggesting that kappa receptor antagonists might have therapeutic utility in the treatment of stress disorders. Three classes of kappa antagonists have been distinguished: non-selective, selective-competitive (readily reversible), and non-competitive (receptor-inactivating); however, which would be the most effective medication has not been established. To assess the utility of receptor inactivating antagonists, we tested the effects of a range of doses in both male and female mice. As previously established, the antinociceptive effects of the kappa agonist U50,488 were blocked by a single injection of the long-acting antagonist norbinatorphimine (norBNI) (10 mg/kg i.p.) in male mice. Ten to 20-fold lower doses of norBNI were ineffective after a single administration, but daily administration of 1.0 or 0.5 mg/kg for 5 days completely blocked U50,488 antinociceptive effects. Daily administration of 0.1 mg/kg norBNI produced slowly accumulating inhibition and completely blocked the antinociceptive effect of U50,488 after 20-30 days. Estrogen reduces female sensitivity to kappa opioid effects, but 30 days of 0.1 mg/kg norBNI completely blocked U50,488 analgesia in ovariectomized mice. Receptor inactivation in both male and female mice treated for 30 days with 0.1 mg/kg norBNI persisted for at least 1-week. These results suggest that receptor-inactivating kappa antagonists are effective in both males and females when given at 100-fold lower doses than typically administered in preclinical studies. The enhanced safety of this low-dosing protocol has important clinical implications if receptor inactivating kappa antagonists advance in medication development.
Learn More >This topical review outlines the resilience pathway to adaptive functioning in pediatric pain within a developmental perspective. Self-Determination Theory proposes that the satisfaction of one's basic psychological needs (for autonomy, relatedness, and competence) is crucial for understanding human flourishing and healthy development. However, the role of the basic psychological needs received little attention in a pediatric-pain population. Yet, we propose that need satisfaction may be a resilience factor and need frustration a risk factor, for living with chronic pain. In this topical review, we first discuss two major models that have been developed to understand pain-related disability: the fear-avoidance model of pain and the ecological resilience-risk model in pediatric chronic pain. Both models have been used with children and adolescents but do not include a developmental perspective. Therefore, we introduce Self-Determination Theory and highlight the potentially moderating and mediating role of the basic needs on pain-related disability in children and adolescents. Taken together, we believe that Self-Determination Theory is compatible with the fear-avoidance model of pain and the ecological resilience-risk model in pediatric chronic pain and may deepen our understanding of why some adolescents are able to live adaptively in spite of chronic pain.
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