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1.
BMC Musculoskelet Disord ; 21(1): 698, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087100

RESUMO

BACKGROUND: Low back pain is common and a significant number of patients experience chronic low back pain. Current treatment options offer small to moderate effects. Patients with vertebral bone marrow lesions visualized as Modic changes on magnetic resonance imaging may represent a subgroup within the low back pain population. There is evidence for inflammatory mediators being involved in development of Modic changes; hence, suppression of inflammation could be a treatment strategy for these patients. This study examines the effect of anti-inflammatory treatment with the TNF-α inhibitor infliximab in patients with chronic low back pain and Modic changes. METHODS/DESIGN: The BackToBasic trial is a multicenter, double blind, randomized controlled trial conducted at six hospitals in Norway, comparing intravenous infusions with infliximab with placebo. One hundred twenty-six patients aged 18-65 with chronic low back pain and type 1 Modic changes will be recruited from secondary care outpatients' clinics. The primary outcome is back pain-specific disability at day 154 (5 months). The study is designed to detect a difference in change of 10 (SD 18) in the Oswestry Disability Index at day 154/ 5 months. The study also aims to refine MRI-assessment, investigate safety and cost-effectiveness and explore the underlying biological mechanisms of Modic changes. DISCUSSION: Finding treatments that target underlying mechanisms could pose new treatment options for patients with low back pain. Suppression of inflammation could be a treatment strategy for patients with low back pain and Modic changes. This paper presents the design of the BackToBasic study, where we will assess the effect of an anti-inflammatory treatment versus placebo in patients with chronic low back pain and type 1 Modic changes. The study is registered at ClinicalTrials.gov under the identifier NCT03704363 . The EudraCT Number: 2017-004861-29.


Assuntos
Dor Crônica , Dor Lombar , Adolescente , Adulto , Idoso , Dor Crônica/diagnóstico por imagem , Dor Crônica/tratamento farmacológico , Humanos , Infliximab/efeitos adversos , Dor Lombar/diagnóstico por imagem , Dor Lombar/tratamento farmacológico , Vértebras Lombares , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Noruega , Medição da Dor , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto Jovem
2.
Antibiotics (Basel) ; 12(7)2023 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-37508313

RESUMO

Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients (n = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study. Gene expression and DNA methylation were investigated at a genome-wide level at screening, after 100 days of treatment, and at one-year follow-up. We identified intra-individual longitudinal changes in gene expression and DNA methylation in patients receiving amoxicillin, while few changes were observed in patients receiving placebo. After 100 days of amoxicillin treatment, 28 genes were significantly differentially expressed, including the downregulation of 19 immunoglobulin genes. At one-year follow-up, the expression levels were still not completely restored. The significant changes in DNA methylation (n = 4548 CpGs) were mainly increased methylation levels between 100 days and one-year follow-up. Hence, the effects on gene expression occurred predominantly during treatment, while the effects on DNA methylation occurred after treatment. In conclusion, unrecognized side effects of long-term amoxicillin treatment were revealed, as alterations were observed in both gene expression and DNA methylation that lasted long after the end of treatment.

3.
J Pain Res ; 16: 1713-1724, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37252109

RESUMO

Objective: Randomized trials testing the effect of antibiotics for chronic low back pain (LBP) with vertebral bone marrow changes on MRI (Modic changes) report inconsistent results. A proposed explanation is subgroups with low grade discitis where antibiotics are effective, but there is currently no method to identify such subgroups. The objective of the present study was to evaluate whether distinct patterns of serum cytokine levels predict any treatment effect of oral amoxicillin at one-year follow-up in patients with chronic low back pain and Modic changes at the level of a previous lumbar disc herniation. Design: We used data from an overpowered, randomized, placebo-controlled trial (the AIM study) that tested 100 days of oral 750 mg amoxicillin vs placebo three times daily in hospital outpatients with chronic (>6 months) LBP with pain intensity ≥5 on a 0-10 numerical rating scale and Modic changes type 1 (oedema type) or 2 (fatty type). We measured serum levels of 40 inflammatory cytokines at baseline and analysed six predefined potential predictors of treatment effect based on cytokine patterns in 78 randomized patients; three analyses with recursive partitioning, one based on cluster analysis and two based on principal component analyses. The primary outcome was the Roland-Morris Disability Questionnaire score at one-year follow-up in the intention to treat population. The methodology and overall results of the AIM study were published previously. Results: The 78 patients were 25-62 years old and 47 (60%) were women. None of the three recursive partitioning analyses resulted in any suggested subgroups. Of all main analyses, the largest effect estimate (mean difference between antibiotic and placebo groups) was seen in a subgroup not predefined as of main interest (Cluster category 3+4; -2.0, 95% CI: -5.2-1.3, RMDQ points; p-value for interaction 0.54). Conclusion: Patterns of inflammatory serum cytokine levels did not predict treatment effect of amoxicillin in patients with chronic LBP and Modic changes. Clinical Trial Registration Number: ClinicalTrials.gov (identifier: NCT02323412).

4.
J Clin Epidemiol ; 151: 75-87, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35926821

RESUMO

OBJECTIVES: The objective of this study was to estimate the minimal important change (MIC) and responsiveness of core patient reported outcome measures for chronic low back pain (LBP) and Modic changes. STUDY DESIGN AND SETTING: In the Antibiotics in Modic changes (AIM) trial we measured disability (RMDQ, ODI), LBP intensity (NRS) and health-related quality of life (EQ5D) electronically at baseline, three- and 12-month follow-up. MICs were estimated using Receiver Operating Curve (ROC) curve and Predictive modeling analyses against the global perceived effect. Credibility of the estimates was assessed by a standardized set of criteria. Responsiveness was assessed by a construct and criterion approach according to COSMIN guidelines. RESULTS: The MIC estimates of RMDQ, ODI and NRS scores varied between a 15-40% reduction, depending on including "slightly improved" in the definition of MIC or not. The MIC estimates for EQ5D were lower. The credibility of the estimates was moderate. For responsiveness, five out of six hypotheses were confirmed and AUC was >0.7 for all PROMs. CONCLUSION: When evaluated in a clinical trial of patients with chronic LBP and Modic changes, MIC thresholds for all PROMs were on the lower spectrum of previous estimates, varying depending on the definition of MIC. Responsiveness was sufficient.


Assuntos
Dor Lombar , Humanos , Avaliação da Deficiência , Dor Lombar/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Inquéritos e Questionários
5.
Sci Rep ; 12(1): 215, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34997115

RESUMO

Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profiling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most inflammatory MC state. We found the expression of 37 genes significantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels significantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identified as significantly enriched among the upregulated genes in all three analyses. Our results point to inflammation and immunological defense as important players in MC biology in patients with chronic LBP.


Assuntos
Medula Óssea/diagnóstico por imagem , Dor Crônica/diagnóstico por imagem , Perfilação da Expressão Gênica , Dor Lombar/diagnóstico por imagem , Imageamento por Ressonância Magnética , Coluna Vertebral/diagnóstico por imagem , Transcriptoma , Adulto , Medula Óssea/imunologia , Dor Crônica/genética , Dor Crônica/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Dor Lombar/genética , Dor Lombar/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Coluna Vertebral/imunologia
6.
RMD Open ; 7(2)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34344830

RESUMO

BACKGROUND: Low back pain (LBP) is a leading cause of disability worldwide, but the aetiology remains poorly understood. Finding relevant biomarkers may lead to better understanding of disease mechanisms. Patients with vertebral endplate bone marrow lesions visualised on MRI as Modic changes (MCs) have been proposed as a distinct LBP phenotype, and inflammatory mediators may be involved in the development of MCs. OBJECTIVES: To identify possible serum biomarkers for LBP in patients with MCs. METHODS: In this case control study serum levels of 40 cytokines were compared between patients with LBP and MC type 1 (n=46) or type 2 (n=37) and healthy controls (n=50). RESULTS: Analyses identified significantly higher levels of six out of 40 cytokines in the MC type 1 group (MC1), and five in the MC type 2 group (MC2) compared with healthy controls. Six cytokines were moderately correlated with pain. Principal component analyses revealed clustering and separation of patients with LBP and controls, capturing 40.8% of the total variance, with 10 cytokines contributing to the separation. Macrophage migration inhibitory factor (MIF) alone accounted for 92% of the total contribution. Further, receiver operating characteristics analysis revealed that MIF showed an acceptable ability to distinguish between patients and controls (area under the curve=0.79). CONCLUSIONS: These results suggest that cytokines may play a role in LBP with MCs. The clinical significance of the findings is unknown. MIF strongly contributed to clustering of patients with LBP with MCs and controls, and might be a biomarker for MCs. Ultimately, these results may guide future research on novel treatments for this patient group.


Assuntos
Dor Lombar , Biomarcadores , Estudos de Casos e Controles , Humanos , Dor Lombar/diagnóstico , Vértebras Lombares/diagnóstico por imagem , Macrófagos
7.
BMJ Open ; 10(6): e035461, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32546490

RESUMO

OBJECTIVE: To evaluate the cost-utility of 100 days of antibiotics in patients with chronic low back pain (LBP) and type I or II Modic changes included in the Antibiotic treatment In patients with chronic low back pain and Modic changes (AIM) study. DESIGN: A cost-utility analysis from a societal and healthcare perspective alongside a double-blinded, parallel group, placebo, multicentre trial. SETTING: Hospital outpatient clinics at six hospitals in Norway. The main results from the AIM study showed a small effect in back-related disability in favour of the antibiotics group, and slightly larger in those with type I Modic changes, but this effect was below the pre-defined threshold for clinically relevant effect. PARTICIPANTS: 180 patients with chronic LBP, previous disc herniation and Modic changes type I (n=118) or type II (n=62) were randomised to antibiotic treatment (n=89) or placebo-control (n=91). INTERVENTIONS: Oral treatment with either 750 mg amoxicillin or placebo three times daily for 100 days. MAIN OUTCOME MEASURES: Quality-adjusted life years (QALYs) by EuroQoL-5D over 12 months and costs for healthcare and productivity loss measured in Euro (€1=NOK 10), in the intention-to-treat population. Cost-utility was expressed in incremental cost-effectiveness ratio (ICER). RESULTS: Mean (SD) total cost was €21 046 (20 105) in the amoxicillin group and €19 076 (19 356) in the placebo group, mean difference €1970 (95% CI; -3835 to 7774). Cost per QALY gained was €24 625. In those with type I Modic changes, the amoxicillin group had higher healthcare consumption than the placebo group, resulting in €39 425 per QALY gained. Given these ICERs and a willingness-to-pay threshold of €27 500 (NOK 275 000), the probability of amoxicillin being cost-effective was 51%. Even when the willingness-to-pay threshold increased to €55 000, the probability of amoxicillin being cost-effective was never higher than 53%. CONCLUSIONS: Amoxicillin treatment showed no evidence of being cost-effective for people with chronic LBP and Modic changes during 1-year follow-up. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02323412.


Assuntos
Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Doenças da Medula Óssea/tratamento farmacológico , Análise Custo-Benefício , Edema/tratamento farmacológico , Dor Lombar/tratamento farmacológico , Dor Lombar/economia , Doença Crônica , Método Duplo-Cego , Humanos , Análise de Intenção de Tratamento , Pessoa de Meia-Idade , Noruega , Medição da Dor , Anos de Vida Ajustados por Qualidade de Vida
8.
BMJ ; 367: l5654, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619437

RESUMO

OBJECTIVE: To assess the efficacy of three months of antibiotic treatment compared with placebo in patients with chronic low back pain, previous disc herniation, and vertebral endplate changes (Modic changes). DESIGN: Double blind, parallel group, placebo controlled, multicentre trial. SETTING: Hospital outpatient clinics at six hospitals in Norway. PARTICIPANTS: 180 patients with chronic low back pain, previous disc herniation, and type 1 (n=118) or type 2 (n=62) Modic changes enrolled from June 2015 to September 2017. INTERVENTIONS: Patients were randomised to three months of oral treatment with either 750 mg amoxicillin or placebo three times daily. The allocation sequence was concealed by using a computer generated number on the prescription. MAIN OUTCOME MEASURES: The primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (range 0-24) at one year follow-up in the intention to treat population. The minimal clinically important between group difference in mean RMDQ score was predefined as 4. RESULTS: In the primary analysis of the total cohort at one year, the difference in the mean RMDQ score between the amoxicillin group and the placebo group was -1.6 (95% confidence interval -3.1 to 0.0, P=0.04). In the secondary analysis, the difference in the mean RMDQ score between the groups was -2.3 (-4.2 to-0.4, P=0.02) for patients with type 1 Modic changes and -0.1 (-2.7 to 2.6, P=0.95) for patients with type 2 Modic changes. Fifty patients (56%) in the amoxicillin group experienced at least one drug related adverse event compared with 31 (34%) in the placebo group. CONCLUSIONS: In this study on patients with chronic low back pain and Modic changes at the level of a previous disc herniation, three months of treatment with amoxicillin did not provide a clinically important benefit compared with placebo. Secondary analyses and sensitivity analyses supported this finding. Therefore, our results do not support the use of antibiotic treatment for chronic low back pain and Modic changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323412.


Assuntos
Amoxicilina , Degeneração do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/complicações , Dor Lombar , Vértebras Lombares , Adulto , Amoxicilina/administração & dosagem , Amoxicilina/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Dor Crônica/diagnóstico , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Avaliação da Deficiência , Método Duplo-Cego , Feminino , Humanos , Dor Lombar/diagnóstico , Dor Lombar/tratamento farmacológico , Dor Lombar/etiologia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Noruega , Medição da Dor/métodos , Resultado do Tratamento
9.
Sleep ; 38(10): 1607-17, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26194577

RESUMO

STUDY OBJECTIVES: Sleep restriction (SR) has been hypothesized to sensitize the pain system. The current study determined whether experimental sleep restriction had an effect on experimentally induced pain and pain-elicited electroencephalographic (EEG) responses. DESIGN: A paired crossover study. INTERVENTION: Pain testing was performed after 2 nights of 50% SR and after 2 nights with habitual sleep (HS). SETTING: Laboratory experiment at research center. PARTICIPANTS: Self-reported healthy volunteers (n = 21, age range: 18-31 y). MEASUREMENTS AND RESULTS: Brief high-density electrical stimuli to the forearm skin produced pinprick-like pain. Subjective pain ratings increased after SR, but only in response to the highest stimulus intensity (P = 0.018). SR increased the magnitude of the pain-elicited EEG response analyzed in the time-frequency domain (P = 0.021). Habituation across blocks did not differ between HS and SR. Event-related desynchronization (ERD) was reduced after SR (P = 0.039). Pressure pain threshold of the trapezius muscle region also decreased after SR (P = 0.017). CONCLUSION: Sleep restriction (SR) increased the sensitivity to pressure pain and to electrically induced pain of moderate, but not low, intensity. The increased electrical pain could not be explained by a difference in habituation. Increased response magnitude is possibly related to reduced processing within the somatosensory cortex after partial SR.


Assuntos
Córtex Cerebral/fisiopatologia , Eletrochoque/efeitos adversos , Dor/fisiopatologia , Privação do Sono/fisiopatologia , Adolescente , Adulto , Estudos Cross-Over , Eletroencefalografia , Feminino , Habituação Psicofisiológica , Voluntários Saudáveis , Humanos , Masculino , Músculo Esquelético/fisiopatologia , Dor/etiologia , Medição da Dor , Limiar da Dor , Pressão/efeitos adversos , Autorrelato , Pele/fisiopatologia , Córtex Somatossensorial/fisiopatologia , Adulto Jovem
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