Pregabalin for pain in fibromyalgia in adults Derry, Sheena; Cording, Malene; Wiffen, Philip J ...
Cochrane database of systematic reviews,
09/2016, Letnik:
2019, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Background
This review updates part of an earlier Cochrane review on 'Pregabalin for acute and chronic pain in adults' (Moore 2009), and considers only fibromyalgia pain.
Antiepileptic drugs have ...been used in pain management since the 1960s. Pregabalin is an antiepileptic drug also used in management of chronic pain conditions, including fibromyalgia. Pain response with pregabalin is associated with major benefits for other symptoms, and improved quality of life and function in people with chronic painful conditions.
Objectives
To assess the analgesic efficacy and adverse events of pregabalin for pain in fibromyalgia in adults, compared with placebo or any active comparator.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE for randomised controlled trials from inception to May 2009 for the original review and to 16 March 2016 for this update. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries.
Selection criteria
We included randomised, double‐blind trials of eight weeks' duration or longer, comparing pregabalin with placebo or another active treatment for relief of pain in fibromyalgia, and reporting on the analgesic effect of pregabalin, with subjective pain assessment by the participant.
Data collection and analysis
Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with moderate pain relief (at least 30% pain relief over baseline or much or very much improved on Patient Global Impression of Change scale (PGIC)) or substantial pain relief (at least 50% pain relief over baseline or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio and number needed to treat (NNT), using standard methods. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 'Summary of findings' tables.
Main results
Our searches identified two new published studies with classic design, and one new published study with an enriched enrolment randomised withdrawal (EERW) design.
We included eight studies. Five (3283 participants) had a classic design in which participants were randomised at the start of the study to pregabalin (150, 300, 450, or 600 mg daily) or placebo, with assessment after 8 to 13 weeks of stable treatment. No studies included active comparators. Studies had low risk of bias, except that the last observation carried forward (LOCF) imputation method used in analyses of the primary outcomes could overestimate treatment effect.
Pregabalin increased the number of participants experiencing substantial benefit (at least 50% pain intensity reduction after 12 or 13 weeks' stable treatment (450 mg: RR 1.8, 95% CI 1.4 to 2.1, 1874 participants, 5 studies, high quality evidence)). Substantial benefit with pregabalin 300 to 600 mg was experienced by about 14% of participants with placebo, but about 9% more with pregabalin 300 to 600 mg (22% to 24%) (high quality evidence). Pregabalin increased the number of participants experiencing moderate benefit (at least 30% pain intensity reduction after 12 or 13 weeks' stable treatment) (450 mg: RR 1.5, 95% CI (1.3 to 1.7), 1874 participants, 5 studies, high quality evidence). Moderate benefit with pregabalin 300 to 600 mg was experienced by about 28% of participants with placebo, but about 11% more with pregabalin 300 to 600 mg (39% to 43%) (high quality evidence). A similar magnitude of effect was found using PGIC of 'very much improved' and 'much or very much improved'. NNTs for these outcomes ranged between 7 and 14 (high quality evidence).
A small study (177 participants) compared nightly with twice‐daily pregabalin, and concluded there was no difference in effect.
Two studies (1492 participants began initial dose titration, 687 participants randomised) had an EERW design in which those with good pain relief after titration were randomised, double blind, to continuing the effective dose (300 to 600 mg pregabalin daily) or a short down‐titration to placebo for 13 or 26 weeks. We calculated the outcome of maintained therapeutic response (MTR) without withdrawal, equivalent to a moderate benefit. Of those randomised, 40% had MTR with pregabalin and 20% with placebo (high quality evidence). The NNT was 5, but normalised to the starting population tested it was 12. About 10% of the initial population would have achieved the MTR outcome, similar to the result from studies of classic design. MTR had no imputation concerns.
The majority (70% to 90%) of participants in all treatment groups experienced adverse events. Specific adverse events were more common with pregabalin than placebo, in particular dizziness, somnolence, weight gain, and peripheral oedema, with number needed to harm of 3.7, 7.4, 18, and 19 respectively for all doses combined (high quality evidence). Serious adverse events did not differ between active treatment groups and placebo (very low quality evidence). Withdrawals for any reason were more common with pregabalin than placebo only with the 600 mg dose in studies of classic design. Withdrawals due to adverse events were about 10% higher with pregabalin than placebo, but withdrawals due to lack of efficacy were about 6% lower (high quality evidence).
Authors' conclusions
Pregabalin 300 to 600 mg produces a major reduction in pain intensity over 12 to 26 weeks with tolerable adverse events for a small proportion of people (about 10% more than placebo) with moderate or severe pain due to fibromyalgia. The degree of pain relief is known to be accompanied by improvements in other symptoms, quality of life, and function. These results are similar to other effective medicines in fibromyalgia (milnacipran, duloxetine).
Physical principles and laws determine the set of possible organismal phenotypes. Constraints arising from development, the environment, and evolutionary history then yield workable, integrated ...phenotypes. We propose a theoretical and practical framework that considers the role of changing environments. This ‘ecomechanical approach’ integrates functional organismal traits with the ecological variables. This approach informs our ability to predict species shifts in survival and distribution and provides critical insights into phenotypic diversity. We outline how to use the ecomechanical paradigm using drag-induced bending in trees as an example. Our approach can be incorporated into existing research and help build interdisciplinary bridges. Finally, we identify key factors needed for mass data collection, analysis, and the dissemination of models relevant to this framework.
All organisms must comply with physical laws, which place rigid or hard constraints on survival and reproduction. Ecomechanics is the expression of that interplay, and assumes a central role when considering organismal development, ecology, and evolution.How organisms will respond to changes in the environment, such as human-mediated climate change, will depend strongly on ecomechanics.Functional traits are commonly used to investigate the consequences of ecological variation. Ecomechanical models that incorporate functional traits and environmental variables are key to deciphering the rules of life and expand upon functional trait studies.The use of the ecomechanical framework is illustrated using multiple examples (e.g., wind-induced bending mechanics in trees and gecko adhesion in the real world). We emphasize safety factors as a key metric when assessing the evolution of form and performance. Biologists can apply our framework to many other systems.We offer suggestions for constructing and tailoring the data pipeline for future ecomechanical models to enhance their availability and utility for various disciplines.
Efforts are being directed to systematically analyze the non-coding regions of the genome for cancer-driving mutations
. cis-regulatory elements (CREs) represent a highly enriched subset of the ...non-coding regions of the genome in which to search for such mutations. Here we use high-throughput chromosome conformation capture techniques (Hi-C) for 19,023 promoter fragments to catalog the regulatory landscape of colorectal cancer in cell lines, mapping CREs and integrating these with whole-genome sequence and expression data from The Cancer Genome Atlas
. We identify a recurrently mutated CRE interacting with the ETV1 promoter affecting gene expression. ETV1 expression influences cell viability and is associated with patient survival. We further refine our understanding of the regulatory effects of copy-number variations, showing that RASL11A is targeted by a previously identified enhancer amplification
. This study reveals new insights into the complex genetic alterations driving tumor development, providing a paradigm for employing chromosome conformation capture to decipher non-coding CREs relevant to cancer biology.
There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we ...conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10
), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10
) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10
), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10
). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.
Diode effects are of great interest for both fundamental physics and modern technologies. Electrical diode effects (nonreciprocal transport) have been observed in Weyl systems. Optical diode effects ...arising from the Weyl fermions have been theoretically considered but not probed experimentally. Here, we report the observation of a nonlinear optical diode effect (NODE) in the magnetic Weyl semimetal CeAlSi, where the magnetization introduces a pronounced directionality in the nonlinear optical second-harmonic generation (SHG). We demonstrate a six-fold change of the measured SHG intensity between opposite propagation directions over a bandwidth exceeding 250 meV. Supported by density-functional theory, we establish the linearly dispersive bands emerging from Weyl nodes as the origin of this broadband effect. We further demonstrate current-induced magnetization switching and thus electrical control of the NODE. Our results advance ongoing research to identify novel nonlinear optical/transport phenomena in magnetic topological materials and further opens new pathways for the unidirectional manipulation of light.
Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new ...GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.
Multiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing ...of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naïve B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alters the expression of genes as candidate non-coding drivers, including copy number variation (CNV) at CREs of MYC and single-nucleotide variants (SNVs) in a PAX5 enhancer. To better inform the interplay between non-coding driver mutations with other driver mechanisms, and their respective roles in oncogenic pathways, we extended our analysis identifying coding drivers in 40 genes, including 11 novel candidates. We demonstrate the same pathways can be targeted by coding and non-coding mutations; exemplified by IRF4 and PRDM1, along with BCL6 and PAX5, genes that are central to plasma cell differentiation. This study reveals new insights into the complex genetic alterations driving MM development and an enhanced understanding of oncogenic pathways.
Abstract
Background
Telomere maintenance is increasingly recognized as being fundamental to glioma oncogenesis with longer leukocyte telomere length (LTL) reported to increase risk of glioma. To gain ...further insight into the relationship between telomere genetics and risk of glioma, we conducted several complementary analyses, using genome-wide association studies data on LTL (78 592 individuals) and glioma (12 488 cases and 18 169 controls).
Methods
We performed both classical and summary Mendelian randomization (SMR), coupled with heterogeneity in dependent instruments tests, at genome-wide significant LTL loci to examine if an association was mediated by the same causal variant in glioma. To prioritize genes underscoring glioma-LTL associations, we analyzed gene expression and DNA methylation data.
Results
Genetically increased LTL was significantly associated with increased glioma risk, random-effects inverse variance weighted ORs per 1 SD unit increase in the putative risk factor (odds ratio ORSD) 4.79 (95% confidence interval: 2.11-10.85; P = 1.76 × 10−4). SMR confirmed the previously reported LTL associations at 3q26.2 (TERC; PSMR = 1.33 × 10−5), 5p15.33 (TERT; PSMR = 9.80 × 10−27), 10q24.33 (STN1 alias OBFC1; PSMR = 4.31 × 10−5), and 20q13.3 (STMN3/RTEL1; PSMR = 2.47 × 10−4) glioma risk loci. Our analysis implicates variation at 1q42.12 (PSMR = 1.55 × 10−2), 6p21.3 (PSMR = 9.76 × 10−3), 6p22.2 (PSMR = 5.45 × 10−3), 7q31.33 (PSMR = 6.52 × 10−3), and 11q22.3 (PSMR = 8.89 × 10−4) as risk factors for glioma risk. While complicated by patterns of linkage disequilibrium, genetic variation involving PARP1, PRRC2A, CARMIL1, POT1, and ATM-NPAT1 was implicated in the etiology of glioma.
Conclusions
These observations extend the role of telomere-related genes in the development of glioma.
Abstract
Despite recent advances in therapy, multiple myeloma essentially remains an incurable malignancy. Targeting tumour-specific essential genes, which constitute a druggable dependency, ...potentially offers a strategy for developing new therapeutic agents to treat MM and overcome drug resistance. To explore this possibility, we analysed DepMap project data identifying 23 MM essential genes and examined the relationship between their expression and patient outcome in three independent series totalling 1503 cases. The expression of
TCF3
and
FLVCR1
were both significantly associated with progression-free survival.
IKBKB
is already a drug target in other diseases, offering the prospect of repurposing to treat MM, while
PIM2
is currently being investigated as a treatment for the disease. Our analysis supports the rationale of using large-scale genetic perturbation screens to guide the development of new therapeutic agents for MM.
Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and ...the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10−13, odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMF expression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMF expression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL.
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•SNP rs539846 underlies 15q15.1 association with chronic lymphocytic leukemia•rs539846 resides in a B cell super-enhancer, disrupting a conserved RELA-binding site•The rs539846 risk allele (A) reduces enhancer activity and RELA binding in CLL•rs539846-A confers lower BMF expression
Kandaswamy et al. find that SNP rs539846 underlies the 15q15.1 chronic lymphocytic leukemia risk locus. Follow-up data demonstrate that rs539846 resides within a transcriptional enhancer and alters RELA binding at a conserved site. The rs539846-A risk allele results in reduced RELA-mediated enhancer activity and lower expression of BCL-2-modifying factor.
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