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Background and aims The ACR1990 criteria of fibromyalgia (FM) have been criticized due to poor reliability of tender points counting (TPC), inconsistent definitions of the widespread pain, and by not considering other symptoms than pain in the FM phenotype. Therefore, several newer self-report measures for FM criteria have emerged. The aim of this study was to translate the fibromyalgia survey questionnaire (FSQ) to Norwegian and validate both the 2011 and the 2016 fibromyalgia survey diagnostic criteria (FSDC) against the ACR1990 criteria. Methods One hundred and twenty chronic pain patients formerly diagnosed with fibromyalgia according to the ACR1990 criteria, and 62 controls not diagnosed or where fibromyalgia was not suspected, were enrolled in this study. All responded to a Norwegian version of the FSQ. Also, they had a clinical examination according to ACR1990 fibromyalgia criteria including a counting of significant tender points with an algometer (TPC). The FSQ with the Widespread Pain Index (WPI) and Symptom Severity scale (SSS) subscales, Fibromyalgia Severity (FS) sum score, was examined for correlations with the fibromyalgia impact questionnaire (FIQ) and TPCs. Face-validity, internal consistence, test-retest reliability and construct validity with convergent and divergent approaches were examined and a Receiver Operating Characteristics (ROC) analysis was performed. Results The internal consistency of FS measured by Cronbach's alfa was good (=0.904). The test-retest reliability measures using intra class correlation were respectable for the FS, including WPI and SSS subscales (0.86, 0.84 and 0.87). FS, WPI and SSS correlated significantly with FIQ (0.74, 0.59 and 0.85) and TPC indicating an adequate construct, convergent validity. The medians of FS, WPI and SSS in the fibromyalgia-group were significantly different from the non-fibromyalgia-group indicating good construct, divergent validity. Using the 2011 and 2016 FSDC vs. ACR 1990 as a reference, sensitivity, specificity, positive likelihood ratio (LR +) and negative likelihood ratio (LR-) were identified. The accuracy rate for both 2011 and 2016 FSDC were respectable (84%). ROC analysis using FS revealed a very good Area Under the Curve (AUC) = 0.860. Conclusion The current study revealed that the Norwegian versions of FSQ is a valid tool for assessment of fibromyalgia according to the 2011 and 2016 (FSDC).
Background and aims The randomized controlled trial (RCT) is currently facing several challenges, one of these being that the placebo response appears to be increasing in RCTs, thereby making it difficult to demonstrate an effect of potentially new treatments over placebo. This problem has primarily been approached by predicting the magnitude of the placebo response via stable factors, such as demographic variables, and/or by developing complex designs aimed at reducing the placebo response in the hope that it will improve the test of the active treatment. Yet, the success of this approach has so far been limited. Methods A new approach toward improving the RCT is put forward based on placebo and nocebo mechanism studies, i.e. studies that investigate the mechanisms underlying placebo analgesia and nocebo hyperalgesia. In a series of meta-analyses the magnitude of placebo and nocebo effects were determined. Experimental studies across nociplastic and neuropathic pain conditions and across pharmacological and acupuncture treatments investigated psychological and neurobiological mechanisms underlying these effects. The obtained results were used to make approximations of expectations to see if that could predict the placebo response in RCTs and function as a new way of tapping into the placebo component of treatment effects. Results The magnitude of placebo and nocebo effects is large and highly variable. Placebo effects exist across chronic pain conditions with varying degrees of known etiology as well as across pharmacological and non-pharmacological treatments. Patients' perception of the treatment, the verbal suggestions given for pain relief, and the patients' expectations toward pain relief contribute to the magnitude of the placebo effect and to pain relief following placebo interventions. Also, unintentional unblinding and patients' perception of a treatment markedly influence the treatment outcome. By making approximations of expectations toward treatment effects it was possible to predict the magnitude of the placebo response in RCTs. Conclusions and implications The new approach of tapping into or directly asking patients about their perception and expectations toward a treatment, along with the account of the natural history of pain, has the potential to improve the information that can be obtained from RCTs. Thus, by interfacing insights from placebo and nocebo mechanism studies, it may be possible to enhance the information that can be obtained from RCTs and to account for a large part of the variability in the placebo component of the overall treatment effect. This approach has the potential to improve the scientific evaluation of treatments, as well as to illustrate how the effect of treatments can be optimized in clinical practice, which is the crux of evidence-based medicine.
αδ proteins are membrane-anchored extracellular glycoproteins which are abundantly expressed in the brain and the peripheral nervous system. They serve as regulatory subunits of voltage-gated calcium channels and, particularly in nerve cells, regulate presynaptic and postsynaptic functions independently from their role as channel subunits. αδ proteins are the targets of the widely prescribed anti-epileptic and anti-allodynic drugs gabapentin and pregabalin, particularly for the treatment of neuropathic pain conditions. Recently, the human genes (CACNA2D1-4) encoding for the four known αδ proteins (isoforms αδ-1 to αδ-4) have been linked to a large variety of neurological and neuropsychiatric disorders including epilepsy, autism spectrum disorders, bipolar disorders, schizophrenia, and depressive disorders. Here, we provide an overview of the hitherto identified disease associations of all known αδ genes, hypothesize on the pathophysiological mechanisms considering their known physiological roles, and discuss the most immanent future research questions. Elucidating their specific physiological and pathophysiological mechanisms may open the way for developing entirely novel therapeutic paradigms for treating brain disorders.
-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) containing GluN2B subunits are prevalent early after birth in most brain regions in rodents. Upon synapse maturation, GluN2B is progressively removed from synapses, which affects NMDAR function and synaptic plasticity. Aberrant recruitment of GluN2B into mature synapses has been implicated in several neuropathologies that afflict adults. We found that the E3 ubiquitin ligase Cbl-b was enriched in the spinal cord dorsal horn neurons of mice and rats and suppressed GluN2B abundance during development and inflammatory pain. Cbl-b abundance increased from postnatal day 1 (P1) to P14, a critical time period for synapse maturation. Through its N-terminal tyrosine kinase binding domain, Cbl-b interacted with GluN2B. Ubiquitination of GluN2B by Cbl-b decreased the synaptic transmission mediated by GluN2B-containing NMDARs. Knocking down Cbl-b in vivo during P1 to P14 led to sustained retention of GluN2B at dorsal horn synapses, suggesting that Cbl-b limits the synaptic abundance of GluN2B in adult mice. However, peripheral inflammation induced by intraplantar injection of complete Freund's adjuvant resulted in the dephosphorylation of Cbl-b at Tyr, which impaired its binding to and ubiquitylation of GluN2B, enabling the reappearance of GluN2B-containing NMDARs at synapses. Expression of a phosphomimic Cbl-b mutant in the dorsal horn suppressed both GluN2B-mediated synaptic currents and manifestations of pain induced by inflammation. The findings indicate a ubiquitin-mediated developmental switch in NMDAR subunit composition that is dysregulated by inflammation, which can enhance nociception.
Emotional approach coping (EAC) is a potentially adaptive emotion-focused coping style that involves understanding or processing one's emotions and expressing them appropriately. Although EAC has been studied in various populations, little is known about this construct among people with chronic pain, including potential mediators such as negative affect, which might link EAC to pain-related variables, and moderators of these relationships.
The aim of this study is to systematically review and critically assess the methodological quality of literature regarding prevalence, characteristics and factors influencing pain, other than phantom limb pain (PLP) in persons with lower limb amputation (LLA). A systematic review was performed (PROSPERO CRD42019138018). Literature was searched using PubMed, EMBASE, PsycINFO, and PEDro. Studies were included if describing pain other than PLP at least three months after amputation. For residual limb pain (RLP) and back pain, a meta-regression was performed. Fifty-one studies were included in which predominantly young males with a unilateral traumatic amputation using a prosthesis were investigated. Pooled prevalence of RLP was 0.51 (95% CI 0.40-0.62) with a positive association with presence of back pain ( = 0.044) in the univariate meta-regression. Pooled prevalence of back pain was 0.55 (95% CI 0.45-0.64), with a positive association of time since amputation ( < 0.001) and co-occurrence of RLP ( = 0.050). Back pain and RLP are common after LLA. The prevalence of back pain was positively associated with the presence of RLP, and vice versa. Future studies should give more attention to other chronic pain types, to persons with a diabetic or vascular cause of amputation, and to pain-related interference.Implications for RehabilitationBoth back pain and residual limb pain occur in more than 50% of persons with lower limb amputation (LLA), and both pain types are positively associated.Clinicians should be aware that chronic pain is common after LLA and can have a significant impact on the functioning of persons with LLA.Future research on this topic should give more attention to other chronic pain types, to persons with a diabetic or vascular cause of amputation, and to pain-related interference.
To review the literature on the mechanism of action of onabotulinumtoxinA in chronic migraine.
Sensory information is transmitted from peripheral nerves, through the spinal cord, and up to the brain. Sensory information may be modulated by projections from the brain to the spinal cord, but the neural substrates for top-down sensory control are incompletely understood. We identified a novel population of inhibitory neurons in the mouse brainstem, distinguished by their expression of prodynorphin, which we named LJA5. Here, we identify a similar group of pdyn+ neurons in the human brainstem, and we define the efferent and afferent projection patterns of LJA5 neurons in mouse. Using specific genetic tools, we selectively traced the projections of the pdyn-expressing LJA5 neurons through the brain and spinal cord. Terminal fields were densest in the lateral and ventrolateral periaqueductal grey (PAG), lateral parabrachial nucleus (LPB), caudal pressor area, and lamina I of the spinal trigeminal nucleus and all levels of the spinal cord. We then labeled cell types in the PAG, LPB, medulla, and spinal cord to better define the specific targets of LJA5 boutons. LJA5 neurons send the only known inhibitory descending projection specifically to lamina I of the spinal cord, which transmits afferent pain, temperature, and itch information up to the brain. Using retrograde tracing, we found LJA5 neurons receive inputs from sensory and stress areas such as somatosensory/insular cortex, preoptic area, paraventricular nucleus, dorsomedial nucleus and lateral hypothalamus, PAG, and LPB. This pattern of inputs and outputs suggest LJA5 neurons are uniquely positioned to be activated by sensation and stress, and in turn, inhibit pain and itch. This article is protected by copyright. All rights reserved.
Female C57BL6 mice exhibit less severe chondropathy compared with male mice. We tests the robustness of this observation and explore underlying mechanisms.