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Mediation analysis is a common statistical method used to investigate mechanisms of health exposure and interventions. The reporting quality of mediation studies used in randomised controlled trials has been considered heterogeneous and incomplete. The reporting quality of mediation analysis in observational studies is unknown. We conducted a systematic review to describe the reporting standards of recently published observational studies that used mediation analysis to understand the mechanism of health exposures. We searched for studies published between June 2017 and June 2019 indexed in EMBASE, MEDLINE and PsycINFO. Two reviewers screened articles and selected a random sample of 50 eligible studies for inclusion. We included studies across 13 healthcare fields and ten different health conditions. Most studies (74%) collected data on healthy individuals to assess their risk of developing a health disorder. Psychosocial and behavioural factors (self-control, self-esteem, alcohol consumption, pain) were the most prevalent exposures (n = 30, 60%), outcomes (n = 23, 46%) and mediators (n = 29, 58%). Most studies used a cross-sectional design (64%, n = 32), and a few studies reported sample size calculations (4%, n = 8). In 20% (n = 10) of the studies, adjustment for confounders was reported. Only 10% (n = 5) of studies reported the assumptions underlying the mediation analysis, and 14% (n = 7) of studies conducted some sensitivity analysis to assess the degree which unmeasured confounders would affect the estimate of the mediation effect. Mediation analysis is a common method used to investigate mechanisms in prevention research. The reporting of mediation analysis in observational studies is incomplete and may impact reproducibility, evidence synthesis and implementation.

Refereed/Peer-reviewed Introduction: Low back pain contributes to an increasing global health burden exacerbated by unsustained improvements from current treatments. There is a need to develop, and test interventions to maintain initial improvements from low back pain treatments. One option is to implement a booster intervention. This study aimed to develop and test the feasibility of implementing a booster intervention delivered remotely to supplement the benefits from a complex intervention for chronic low back pain. Method: This study was nested in the RESOLVE trial. The booster intervention was developed by an expert group, including a clinical psychologist, exercise physiologist and physiotherapists, and based on a motivational interviewing framework. We developed a conversational flow chart to support the clinician to guide participants towards achieving their pre-specified personal goals and future low back pain self-management. Participants with chronic low back pain who were aged over 18 years and fluent in English were recruited. The booster intervention was delivered in one session, remotely, by telephone. The intervention was considered feasible if: participants were able to be contacted or 7/10. Results: Fifty participants with chronic non-specific low back pain were recruited to test the feasibility of implementing the booster intervention. Less than three contact attempts were necessary to arrange the booster session, only one participant declined to participate. Participants perceived the session to be beneficial; on a 0 to 10 scale of perceived benefit, the average score recorded was 8.3 (SD 2.0). Clinicians also reported a moderate perceived benefit to the participant; the average score recorded by clinicians was 6.3 (SD 1.6). Conclusion: We developed a step by step, simple booster intervention that was perceived to be beneficial to participants with chronic low back pain. The booster can feasibly be delivered remotely following a complex intervention.

Objectives This meta-analysis aims to investigate the efficacy and safety of medicines that target neurotrophic factors for low back pain (LBP) or sciatica. Methods We searched published and trial registry reports of randomized controlled trials evaluating the effect of medicines that target neurotrophic factors to LBP or sciatica in seven databases from inception to December 2020. Two reviewers independently identified studies, extracted data, and assessed the risk of bias and certainty in the evidence. Results Nine studies (3370 participants) were included in the meta-analyses. Low certainty evidence showed that anti-nerve growth factor (NGF) may reduce pain at 4 weeks (mean difference [MD] −6.75, 95% CI: −8.61, −4.90) and 12 weeks (MD −6.16, 95% CI: −8.38, −3.94), and may increase adverse effects for chronic LBP (odds ratio [OR] 1.18, 95% CI: 1.01, 1.38). Higher doses of anti-NGF may offer a clinically important reduction in pain at the cost of increased adverse effects for chronic LBP. Very low certainty evidence showed that anti-NGF and glial cell line-derived neurotrophic factor (pro-GDNF) may not reduce pain for sciatica at 4 weeks (MD −1.40, 95% CI: −8.26, 5.46), at 12 weeks (MD −2.91, 95% CI: −13.69, 7.67) and may increase adverse effects for sciatica (OR 3.27, 95% CI: 1.78, 6.00). Conclusion Anti-NGF may offer small reductions in pain intensity for chronic LBP. The effect may depend on the dose and types of medicines. For sciatica, anti-NGF or pro-GDNF may not reduce pain. Medicines that target neurotrophic factors for LBP or sciatica are associated with different adverse effects compared to those observed in commonly prescribed medicines for these conditions.

IntroductionKnee osteoarthritis is a leading cause of disability, resulting in pain and reduced quality of life. Exercise is the cornerstone of conservative management but effects are, at best, moderate. Early evidence suggests that repetitive transcranial magnetic stimulation (rTMS) applied over the primary motor cortex (M1) may improve the effect of exercise in knee osteoarthritis. This pilot study aims to (1) determine the feasibility, safety and participant-rated response to an intervention adding M1 rTMS to exercise in knee osteoarthritis; (2) elucidate physiological mechanisms in response to the intervention; (3) provide data to conduct a sample size calculation for a fully powered trial.Methods and analysisThis is a pilot randomised, assessor-blind, therapist-blind and participant-blind, sham-controlled trial. Thirty individuals with painful knee osteoarthritis will be recruited and randomly allocated to receive either: (1) active rTMS+exercise or (2) sham rTMS+exercise intervention. Participants will receive 15 min of either active or sham rTMS immediately prior to 30 min of supervised muscle strengthening exercise (2×/week, 6 weeks) and complete unsupervised home exercises. Outcome measures of feasibility, safety, pain, function and physiological mechanisms will be assessed before and/or after the intervention. Feasibility and safety will be analysed using descriptive analysis. Within-group and between-group comparisons of pain and function will be conducted to examine trends of efficacy.Ethics and disseminationThis study has been approved by the University of New South Wales Human Research Ethics Committee (HC210954). All participants will provide written informed consent. The study results will be submitted for peer-reviewed publication.Trial registration numberACTRN12621001712897p.

BACKGROUND Pain catastrophizing underpins several psychosocial theories of pain, but there is limited evidence to support the proposal that changes in pain catastrophizing cause changes in pain. Results from mediation analyses have conflicting results, and one reason for these might be the timing of the assessment of pain catastrophizing. This study aimed to test the effect of the timing of the assessment of pain catastrophizing on its mediating role on pain intensity. METHODS Causal mediation analysis using data from a randomized controlled trial which included 100 participants with chronic low back pain. The trial found that clinical hypnosis, compared to pain education, reduced worst pain intensity and pain catastrophizing. In model 1, we used data from 2-week follow-up for pain catastrophizing and 3-month follow-up for pain. In model 2, we used data from 3-month follow-up for both pain catastrophizing and pain. RESULTS The intervention had a significant average total effect on pain (-1.34 points, 95% CI -2.50 to -0.13). The average causal mediation effect was significant when pain catastrophizing, and pain were measured at the same time (-0.62 points, 95% CI -1.30 to -0.11) but not significant when pain catastrophizing and pain intensity were measured at different times (-0.10 points, 95% CI -0.42 to 0.09). CONCLUSIONS The timing of the assessment influenced the mediating role of pain catastrophizing on pain intensity. These results raise questions on the casual role that pain catastrophizing has on pain intensity. Psychosocial interventions such as clinical hypnosis can reduce pain intensity even when there has been no change in pain catastrophizing.

Background Antidepressant medicines are used to manage symptoms of low back pain. The efficacy, acceptability, and safety of antidepressant medicines for low back pain (LBP) are not clear. We aimed to evaluate the efficacy, acceptability, and safety of antidepressant medicines for LBP. Methods We searched CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, the EU Clinical Trials Register, and the WHO International Clinical Trial Registry Platform from inception to May 2020. We included published and trial registry reports of RCTs that allocated adult participants with LBP to receive an antidepressant medicine or a placebo medicine. Pairs of authors independently extracted data in duplicate. We extracted participant characteristics, study sample size, outcome values, and measures of variance for each outcome. We data using random-effects meta-analysis models and calculated estimates of effects and heterogeneity for each outcome. We formed judgments of confidence in the evidence in accordance with GRADE. We report our findings in accordance with the PRISMA statement. We prespecified all outcomes in a prospectively registered protocol. The primary outcomes were pain intensity and acceptability. We measured pain intensity at end-of-treatment on a 0–100 point scale and considered 10 points the minimal clinically important difference. We defined acceptability as the odds of stopping treatment for any reason. Results We included 23 RCTs in this review. Data were available for pain in 17 trials and acceptability in 14 trials. Treatment with antidepressants decreased pain intensity by 4.33 points (95% CI − 6.15 to − 2.50) on a 0–100 scale, compared to placebo. Treatment with antidepressants increased the odds of stopping treatment for any reason (OR 1.27 [95% CI 1.03 to 1.56]), compared to placebo. Conclusions Treatment of LBP with antidepressants is associated with small reductions in pain intensity and increased odds of stopping treatment for any reason, compared to placebo. The effect on pain is not clinically important. The effect on acceptability warrants consideration. These findings provide Level I evidence to guide clinicians in their use of antidepressants to treat LBP. Trial registration We prospectively registered the protocol for this systematic review on PROSPERO (CRD42020149275).

Refereed/Peer-reviewed Importance: The effects of altered neural processing, defined as altering neural networks responsible for perceptions of pain and function, on chronic pain remains unclear. Objective: To estimate the effect of a graded sensorimotor retraining intervention (RESOLVE) on pain intensity in people with chronic low back pain. Design, Setting, and Participants: This parallel, 2-group, randomized clinical trial recruited participants with chronic (>3 months) nonspecific low back pain from primary care and community settings. A total of 276 adults were randomized (in a 1:1 ratio) to the intervention or sham procedure and attention control groups delivered by clinicians at a medical research institute in Sydney, Australia. The first participant was randomized on December 10, 2015, and the last was randomized on July 25, 2019. Follow-up was completed on February 3, 2020. Interventions: Participants randomized to the intervention group (n = 138) were asked to participate in 12 weekly clinical sessions and home training designed to educate them about and assist them with movement and physical activity while experiencing lower back pain. Participants randomized to the control group (n = 138) were asked to participate in 12 weekly clinical sessions and home training that required similar time as the intervention but did not focus on education, movement, and physical activity. The control group included sham laser and shortwave diathermy applied to the back and sham noninvasive brain stimulation. Main Outcomes and Measures: The primary outcome was pain intensity at 18 weeks, measured on an 11-point numerical rating scale (range, 0 [no pain] to 10 [worst pain imaginable]) for which the between-group minimum clinically important difference is 1.0 point. Results: Among 276 randomized patients (mean [SD] age, 46 [14.3] years; 138 [50%] women), 261 (95%) completed follow-up at 18 weeks. The mean pain intensity was 5.6 at baseline and 3.1 at 18 weeks in the intervention group and 5.8 at baseline and 4.0 at 18 weeks in the control group, with an estimated between-group mean difference at 18 weeks of -1.0 point ([95% CI, -1.5 to -0.4]; P =.001), favoring the intervention group. Conclusions and Relevance: In this randomized clinical trial conducted at a single center among patients with chronic low back pain, graded sensorimotor retraining, compared with a sham procedure and attention control, significantly improved pain intensity at 18 weeks. The improvements in pain intensity were small, and further research is needed to understand the generalizability of the findings. Trial Registration: ANZCTR Identifier: ACTRN12615000610538.

Objective To investigate the efficacy, acceptability, and safety of muscle relaxants for low back pain. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, CINAHL, CENTRAL, ClinicalTrials.gov, clinicialtrialsregister.eu, and WHO ICTRP from inception to 23 February 2021. Eligibility criteria for study selection Randomised controlled trials of muscle relaxants compared with placebo, usual care, waiting list, or no treatment in adults (≥18 years) reporting non-specific low back pain. Data extraction and synthesis Two reviewers independently identified studies, extracted data, and assessed the risk of bias and certainty of the evidence using the Cochrane risk-of-bias tool and Grading of Recommendations, Assessment, Development and Evaluations, respectively. Random effects meta-analytical models through restricted maximum likelihood estimation were used to estimate pooled effects and corresponding 95% confidence intervals. Outcomes included pain intensity (measured on a 0-100 point scale), disability (0-100 point scale), acceptability (discontinuation of the drug for any reason during treatment), and safety (adverse events, serious adverse events, and number of participants who withdrew from the trial because of an adverse event). Results 49 trials were included in the review, of which 31, sampling 6505 participants, were quantitatively analysed. For acute low back pain, very low certainty evidence showed that at two weeks or less non-benzodiazepine antispasmodics were associated with a reduction in pain intensity compared with control (mean difference −7.7, 95% confidence interval−12.1 to−3.3) but not a reduction in disability (−3.3, −7.3 to 0.7). Low and very low certainty evidence showed that non-benzodiazepine antispasmodics might increase the risk of an adverse event (relative risk 1.6, 1.2 to 2.0) and might have little to no effect on acceptability (0.8, 0.6 to 1.1) compared with control for acute low back pain, respectively. The number of trials investigating other muscle relaxants and different durations of low back pain were small and the certainty of evidence was reduced because most trials were at high risk of bias. Conclusions Considerable uncertainty exists about the clinical efficacy and safety of muscle relaxants. Very low and low certainty evidence shows that non-benzodiazepine antispasmodics might provide small but not clinically important reductions in pain intensity at or before two weeks and might increase the risk of an adverse event in acute low back pain, respectively. Large, high quality, placebo controlled trials are urgently needed to resolve uncertainty. Systematic review registration PROSPERO CRD42019126820 and Open Science Framework https://osf.io/mu2f5/ .

Background Chronic low back pain (CLBP) is a global health problem associated with an increasing burden on individuals, health care systems, and society. Common treatments for people with CLBP produce, on average, small short-term improvements in pain and function compared with minimal care. The RESOLVE trial randomly allocated 276 people with CLBP to a new complex treatment strategy, pain education integrated with graded sensorimotor precision training (RESOLVE), or a sham control. The RESOLVE treatment was developed within a theoretical framework to target possible treatment mechanisms associated with CLBP development and persistence. Objective This protocol describes the planned evaluation of these proposed treatment mechanisms. Improved understanding of the mechanisms underpinning the RESOLVE treatment may guide its refinement and implementation. Methods We will use causal mediation analysis to evaluate the proposed treatment mechanisms, including pain self-efficacy, back beliefs, pain catastrophizing, kinesiophobia, back perception, tactile acuity, and movement coordination. The primary outcomes are pain intensity and function at 18 weeks following allocation. Data were collected blind to allocation and hypotheses at baseline (mediators, outcomes, confounders), end of treatment (mediators), and at 18 weeks following allocation (outcomes). We will test the robustness of our findings by conducting planned sensitivity analyses. Results Ethical approval was granted by the University of New South Wales Human Research Ethics Committee (HC15357). A total of 276 participants have been recruited from primary care practices and the community in Sydney, Australia. Conclusions The RESOLVE treatment constitutes a new paradigm for CLBP management with potentially wide-reaching implications. This mechanistic evaluation will provide evidence for the hypothesized treatment mechanisms and help explain why the treatment strategy did or did not have an effect on patient-reported outcomes. These results will help guide the treatment refinement and implementation. Trial Registration Australian and New Zealand Clinical Trials Registry ACTRN12615000610538; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368619&isReview=true International Registered Report Identifier (IRRID) DERR1-10.2196/26053

BACKGROUND Low back pain (LBP) is the leading cause of years lived with disability worldwide. Most people with LBP receive the diagnosis of nonspecific LBP or sciatica. Medications are commonly prescribed but have limited analgesic effects and are associated with adverse events. A novel treatment approach is to target neurotrophins such as nerve growth factor (NGF) to reduce pain intensity. NGF inhibitors have been tested in some randomized controlled trials (RCTs) in recent years, showing promise for the treatment of chronic LBP; however, their efficacy and safety need to be evaluated to guide regulatory actions. OBJECTIVE The aim of this study is to evaluate the efficacy and safety of medicines targeting neurotrophins in patients with LBP and sciatica. METHODS In this systematic review, we will include published and unpublished records of parallel RCTs and the first phase of crossover RCTs that compare the effects of medicines targeting neurotrophins with any control group. We will search the CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, EU Clinical Trials Register, and WHO International Clinical Registry Platform databases from inception. Pairs of authors will independently screen the records for eligibility, and we will independently extract data in duplicate. We will conduct a quantitative synthesis (meta-analysis) with the studies that report sufficient data and compare the medicines of interest versus placebo. We will use random-effects models and calculate estimates of effects and heterogeneity for each outcome. We will assess the risk of bias for each study using the Cochrane Collaboration tool, and form judgments of confidence in the evidence according to GRADE recommendations. We will use the PRISMA statement to report the findings. We plan to conduct subgroup analyses by condition, type of medication, and time point. We will also assess the impact of a potential new trial on an existing meta-analysis. Data from studies that meet inclusion criteria but cannot be included in the meta-analysis will be reported narratively. RESULTS The protocol was registered on the Open Science Framework on May 19, 2020. As of December 2020, we have identified 1932 records. CONCLUSIONS This systematic review and meta-analysis will assess the evidence for the efficacy and safety of NGF inhibitors for pain in patients with nonspecific LBP and sciatica. The inclusion of new studies and unpublished data may improve the precision of the effect estimates and guide regulatory actions of the medications for LBP and sciatica. CLINICALTRIAL Open Science Framework; https://osf.io/b8adn/ INTERNATIONAL REGISTERED REPORT DERR1-10.2196/22905

Background Statistical analysis plans describe the planned data management and analysis for clinical trials. This supports transparent reporting and interpretation of clinical trial results. This paper reports the statistical analysis plan for the RESOLVE clinical trial. The RESOLVE trial assigned participants with chronic low back pain to graded sensory-motor precision training or sham-control. Results We report the planned data management and analysis for the primary and secondary outcomes. The primary outcome is pain intensity at 18-weeks post randomization. We will use mixed-effects models to analyze the primary and secondary outcomes by intention-to-treat. We will report adverse effects in full. We also describe analyses if there is non-adherence to the interventions, data management procedures, and our planned reporting of results. Conclusion This statistical analysis plan will minimize the potential for bias in the analysis and reporting of results from the RESOLVE trial. Trial registration ACTRN12615000610538 ( https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368619 ).

Background Exercise is recommended for the management of chronic low back pain (CLBP). Trialists have proposed numerous mechanisms to explain why exercise improves pain and function in people with CLBP, but these are yet to be synthesised. Objective To synthesise the proposed mechanisms of benefit for exercise in people with CLBP. Design Review. Methods The Physiotherapy Evidence Database (PEDro) was searched from inception to July 2019. Randomised controlled trials of adults with CLBP, indexed in PEDro as ‘fitness training’, were included. Two reviewers independently screened and extracted data from each study. Data were analysed quantitatively and qualitatively using thematic analysis. Results 186 studies were identified and 110 were included in the analysis. Thirty-six studies (33%) did not provide a mechanism of benefit for exercise in people with CLBP. Of the remaining studies, most provided more than one mechanism, from which 33 unique mechanisms were identified. These were grouped into five themes which, from most to least common, were: neuromuscular (n = 105 (44%)); psychosocial (n = 87 (36%)); neurophysiological (n = 22 (9%)); cardiometabolic (n = 15 (6%)); and tissue healing (n = 12 (5%)). The effects of these proposed mechanisms on outcomes for people with CLBP were seldom examined. Conclusions This review identified a variety of mechanisms proposed in clinical trials to explain why ‘fitness training’ works for people with CLBP, but these mechanisms were seldom tested. Randomised controlled trials investigating the mediating effects of these mechanisms may be warranted to better understand why exercise works for CLBP.

Background Low back pain (LBP) is the leading cause of years lived with disability worldwide. Most people with LBP receive the diagnosis of nonspecific LBP or sciatica. Medications are commonly prescribed but have limited analgesic effects and are associated with adverse events. A novel treatment approach is to target neurotrophins such as nerve growth factor (NGF) to reduce pain intensity. NGF inhibitors have been tested in some randomized controlled trials (RCTs) in recent years, showing promise for the treatment of chronic LBP; however, their efficacy and safety need to be evaluated to guide regulatory actions. Objective The aim of this study is to evaluate the efficacy and safety of medicines targeting neurotrophins in patients with LBP and sciatica. Methods In this systematic review, we will include published and unpublished records of parallel RCTs and the first phase of crossover RCTs that compare the effects of medicines targeting neurotrophins with any control group. We will search the CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, EU Clinical Trials Register, and WHO International Clinical Registry Platform databases from inception. Pairs of authors will independently screen the records for eligibility, and we will independently extract data in duplicate. We will conduct a quantitative synthesis (meta-analysis) with the studies that report sufficient data and compare the medicines of interest versus placebo. We will use random-effects models and calculate estimates of effects and heterogeneity for each outcome. We will assess the risk of bias for each study using the Cochrane Collaboration tool, and form judgments of confidence in the evidence according to GRADE recommendations. We will use the PRISMA statement to report the findings. We plan to conduct subgroup analyses by condition, type of medication, and time point. We will also assess the impact of a potential new trial on an existing meta-analysis. Data from studies that meet inclusion criteria but cannot be included in the meta-analysis will be reported narratively. Results The protocol was registered on the Open Science Framework on May 19, 2020. As of December 2020, we have identified 1932 records. Conclusions This systematic review and meta-analysis will assess the evidence for the efficacy and safety of NGF inhibitors for pain in patients with nonspecific LBP and sciatica. The inclusion of new studies and unpublished data may improve the precision of the effect estimates and guide regulatory actions of the medications for LBP and sciatica. Trial Registration Open Science Framework; https://osf.io/b8adn/ International Registered Report Identifier (IRRID) DERR1-10.2196/22905

The potential benefits of combining pain education (PE) with clinical hypnosis (CH) has not yet been investigated in individuals with chronic pain. A total of 100 patients with chronic nonspecific low back pain were randomized to receive either: 1) PE alone, or 2) PE with CH. Outcomes were collected by a blinded assessor at 2 weeks and 3 months after randomization. The primary outcomes were average pain intensity, worst pain intensity (both assessed with 11-point numeric rating scales), and disability (24-item Roland Morris Disability Questionnaire) at 2 weeks. At 2 weeks, participants who received PE with CH reported lower worst pain intensity (mean difference = 1.35 points, 95% confidence interval [CI] = .32–2.37) and disability (mean difference = 2.34 points, 95% CI = .06–4.61), but not average pain intensity (mean difference = .67 point, 95% CI = −.27 to 1.62), relative to participants who received PE alone. PE with CH participants also reported more global perceived benefits at 2 weeks (mean difference = −1.98 points, 95% CI = −3.21 to −.75). At 3 months, participants who received PE with CH reported lower worst pain intensity (mean difference = 1.32 points, 95% CI = .29–2.34) and catastrophizing (mean difference = 5.30 points, 95% CI = 1.20–9.41). No adverse effects in either treatment condition were reported. To our knowledge, this is the first trial showing that additional use of hypnosis with PE results in improved outcomes over PE alone in patients with chronic nonspecific low back pain. Perspective This study provides evidence supporting the efficacy of another treatment option for teaching patients to self-manage chronic low back pain that has a relatively low cost and that can be offered in groups.