A home-based self-directed EEG neurofeedback intervention for people with chronic neuropathic pain following spinal cord injury (the StoPain Trial): description of the intervention.

STUDY DESIGN: Randomised controlled trial. OBJECTIVES: The objective is to describe an electroencephalography (EEG) neurofeedback intervention that will be provided in a randomised controlled trial for people with neuropathic pain following spinal cord injury (SCI): the StoPain Trial. In this trial, participants in the treatment group will implement an EEG neurofeedback system as an analgesic intervention at home, while participants in the control group will continue with the treatments available to them in the community. SETTING: University-based study in Sydney, Australia. METHODS/RESULTS: This manuscript describes the rationale and components of the EEG neurofeedback intervention designed for individuals with SCI neuropathic pain and intended for home-based implementation. Our report is based on the criteria of the Template for Intervention Description and Replication (TIDieR) checklist, and includes why the efficacy of EEG neurofeedback will be investigated, what will be provided, who will administer it, and how, where, when, and how much the EEG neurofeedback intervention will be administered. CONCLUSIONS: This manuscript provides a detailed description of a complex intervention used in a randomised controlled trial. This description will facilitate the subsequent interpretation of the trial results and allow for the replication of the intervention in clinical practice and future trials. SPONSORSHIP: Australian Government Medical Research Future Fund (2020 Rare Cancers Rare Diseases and Unmet Needs Scheme: 2006020).

Mechanisms of vocational interventions for return to work from musculoskeletal conditions: a mediation analysis of the MI-NAV trial.

OBJECTIVES: To investigate whether and to what extent, return to work (RTW) expectancy and workability mediate the effect of two vocational interventions on reducing sickness absence in workers on sick leave from a musculoskeletal condition. METHODS: This is a preplanned mediation analysis of a three-arm parallel randomised controlled trial which included 514 employed working adults with musculoskeletal conditions on sick leave for at least 50% of their contracted work hours for ≥7 weeks. Participants were randomly allocated (1:1:1) to one of three treatment arms; usual case management (UC) (n=174), UC plus motivational interviewing (MI) (n=170) and UC plus a stratified vocational advice intervention (SVAI) (n=170). The primary outcome was the number of sickness absence days over 6 months from randomisation. Hypothesised mediators included RTW expectancy and workability assessed 12 weeks after randomisation. RESULTS: The mediated effect of the MI arm compared with UC on sickness absence days through RTW expectancy was -4.98 days (-8.89 to -1.04), and workability was -3.17 days (-8.55 to 2.32). The mediated effect of the SVAI arm compared with UC on sickness absence days through RTW expectancy was -4.39 days (-7.60 to -1.47), and workability was -3.21 days (-7.90 to 1.50). The mediated effects for workability were not statistically significant. CONCLUSIONS: Our study provides new evidence for the mechanisms of vocational interventions to reduce sickness absence related to sick leave due to musculoskeletal conditions. Changing an individual's expectation that RTW is likely may result in meaningful reductions in sickness absence days. TRIAL REGISTRATION NUMBER: NCT03871712.

Pharmacological treatments for low back pain in adults: an overview of Cochrane Reviews.

BACKGROUND: Pharmacological interventions are the most used treatment for low back pain (LBP). Use of evidence from systematic reviews of the effects of pharmacological interventions for LBP published in the Cochrane Library, is limited by lack of a comprehensive overview. OBJECTIVES: To summarise the evidence from Cochrane Reviews of the efficacy, effectiveness, and safety of systemic pharmacological interventions for adults with non-specific LBP. METHODS: The Cochrane Database of Systematic Reviews was searched from inception to 3 June 2021, to identify reviews of randomised controlled trials (RCTs) that investigated systemic pharmacological interventions for adults with non-specific LBP. Two authors independently assessed eligibility, extracted data, and assessed the quality of the reviews and certainty of the evidence using the AMSTAR 2 and GRADE tools. The review focused on placebo comparisons and the main outcomes were pain intensity, function, and safety. MAIN RESULTS: Seven Cochrane Reviews that included 103 studies (22,238 participants) were included. There is high confidence in the findings of five reviews, moderate confidence in one, and low confidence in the findings of another. The reviews reported data on six medicines or medicine classes: paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, benzodiazepines, opioids, and antidepressants. Three reviews included participants with acute or sub-acute LBP and five reviews included participants with chronic LBP. Acute LBP Paracetamol There was high-certainty evidence for no evidence of difference between paracetamol and placebo for reducing pain intensity (MD 0.49 on a 0 to 100 scale (higher scores indicate worse pain), 95% CI -1.99 to 2.97), reducing disability (MD 0.05 on a 0 to 24 scale (higher scores indicate worse disability), 95% CI -0.50 to 0.60), and increasing the risk of adverse events (RR 1.07, 95% CI 0.86 to 1.33). NSAIDs There was moderate-certainty evidence for a small between-group difference favouring NSAIDs compared to placebo at reducing pain intensity (MD -7.29 on a 0 to 100 scale (higher scores indicate worse pain), 95% CI -10.98 to -3.61), high-certainty evidence for a small between-group difference for reducing disability (MD -2.02 on a 0-24 scale (higher scores indicate worse disability), 95% CI -2.89 to -1.15), and very low-certainty evidence for no evidence of an increased risk of adverse events (RR 0.86, 95% CI 0. 63 to 1.18). Muscle relaxants and benzodiazepines There was moderate-certainty evidence for a small between-group difference favouring muscle relaxants compared to placebo for a higher chance of pain relief (RR 0.58, 95% CI 0.45 to 0.76), and higher chance of improving physical function (RR 0.55, 95% CI 0.40 to 0.77), and increased risk of adverse events (RR 1.50, 95% CI 1. 14 to 1.98). Opioids None of the included Cochrane Reviews aimed to identify evidence for acute LBP. Antidepressants No evidence was identified by the included reviews for acute LBP. Chronic LBP Paracetamol No evidence was identified by the included reviews for chronic LBP. NSAIDs There was low-certainty evidence for a small between-group difference favouring NSAIDs compared to placebo for reducing pain intensity (MD -6.97 on a 0 to 100 scale (higher scores indicate worse pain), 95% CI -10.74 to -3.19), reducing disability (MD -0.85 on a 0-24 scale (higher scores indicate worse disability), 95% CI -1.30 to -0.40), and no evidence of an increased risk of adverse events (RR 1.04, 95% CI -0.92 to 1.17), all at intermediate-term follow-up (> 3 months and ≤ 12 months postintervention). Muscle relaxants and benzodiazepines There was low-certainty evidence for a small between-group difference favouring benzodiazepines compared to placebo for a higher chance of pain relief (RR 0.71, 95% CI 0.54 to 0.93), and low-certainty evidence for no evidence of difference between muscle relaxants and placebo in the risk of adverse events (RR 1.02, 95% CI 0.67 to 1.57). Opioids There was high-certainty evidence for a small between-group difference favouring tapentadol compared to placebo at reducing pain intensity (MD -8.00 on a 0 to 100 scale (higher scores indicate worse pain), 95% CI -1.22 to -0.38), moderate-certainty evidence for a small between-group difference favouring strong opioids for reducing pain intensity (SMD -0.43, 95% CI -0.52 to -0.33), low-certainty evidence for a medium between-group difference favouring tramadol for reducing pain intensity (SMD -0.55, 95% CI -0.66 to -0.44) and very low-certainty evidence for a small between-group difference favouring buprenorphine for reducing pain intensity (SMD -0.41, 95% CI -0.57 to -0.26). There was moderate-certainty evidence for a small between-group difference favouring strong opioids compared to placebo for reducing disability (SMD -0.26, 95% CI -0.37 to -0.15), moderate-certainty evidence for a small between-group difference favouring tramadol for reducing disability (SMD -0.18, 95% CI -0.29 to -0.07), and low-certainty evidence for a small between-group difference favouring buprenorphine for reducing disability (SMD -0.14, 95% CI -0.53 to -0.25). There was low-certainty evidence for a small between-group difference for an increased risk of adverse events for opioids (all types) compared to placebo; nausea (RD 0.10, 95% CI 0.07 to 0.14), headaches (RD 0.03, 95% CI 0.01 to 0.05), constipation (RD 0.07, 95% CI 0.04 to 0.11), and dizziness (RD 0.08, 95% CI 0.05 to 0.11). Antidepressants There was low-certainty evidence for no evidence of difference for antidepressants (all types) compared to placebo for reducing pain intensity (SMD -0.04, 95% CI -0.25 to 0.17) and reducing disability (SMD -0.06, 95% CI -0.40 to 0.29). AUTHORS' CONCLUSIONS: We found no high- or moderate-certainty evidence that any investigated pharmacological intervention provided a large or medium effect on pain intensity for acute or chronic LBP compared to placebo. For acute LBP, we found moderate-certainty evidence that NSAIDs and muscle relaxants may provide a small effect on pain, and high-certainty evidence for no evidence of difference between paracetamol and placebo. For safety, we found very low- and high-certainty evidence for no evidence of difference with NSAIDs and paracetamol compared to placebo for the risk of adverse events, and moderate-certainty evidence that muscle relaxants may increase the risk of adverse events. For chronic LBP, we found low-certainty evidence that NSAIDs and very low- to high-certainty evidence that opioids may provide a small effect on pain. For safety, we found low-certainty evidence for no evidence of difference between NSAIDs and placebo for the risk of adverse events, and low-certainty evidence that opioids may increase the risk of adverse events.

Interventions for treating pain and disability in adults with complex regional pain syndrome- an overview of systematic reviews.

BACKGROUND: Complex regional pain syndrome (CRPS) is a chronic pain condition that usually occurs in a limb following trauma or surgery. It is characterised by persisting pain that is disproportionate in magnitude or duration to the typical course of pain after similar injury. There is currently no consensus regarding the optimal management of CRPS, although a broad range of interventions have been described and are commonly used. This is the first update of the original Cochrane review published in Issue 4, 2013. OBJECTIVES: To summarise the evidence from Cochrane and non-Cochrane systematic reviews of the efficacy, effectiveness, and safety of any intervention used to reduce pain, disability, or both, in adults with CRPS. METHODS: We identified Cochrane reviews and non-Cochrane reviews through a systematic search of Ovid MEDLINE, Ovid Embase, Cochrane Database of Systematic Reviews, CINAHL, PEDro, LILACS and Epistemonikos from inception to October 2022, with no language restrictions. We included systematic reviews of randomised controlled trials that included adults (≥18 years) diagnosed with CRPS, using any diagnostic criteria.  Two overview authors independently assessed eligibility, extracted data, and assessed the quality of the reviews and certainty of the evidence using the AMSTAR 2 and GRADE tools respectively. We extracted data for the primary outcomes pain, disability and adverse events, and the secondary outcomes quality of life, emotional well-being, and participants' ratings of satisfaction or improvement with treatment.  MAIN RESULTS: We included six Cochrane and 13 non-Cochrane systematic reviews in the previous version of this overview and five Cochrane and 12 non-Cochrane reviews in the current version. Using the AMSTAR 2 tool, we judged Cochrane reviews to have higher methodological quality than non-Cochrane reviews. The studies in the included reviews were typically small and mostly at high risk of bias or of low methodological quality. We found no high-certainty evidence for any comparison.  There was low-certainty evidence that bisphosphonates may reduce pain intensity post-intervention (standardised mean difference (SMD) -2.6, 95% confidence interval (CI) -1.8 to -3.4, P = 0.001; I2 = 81%; 4 trials, n = 181) and moderate-certainty evidence that they are probably associated with increased adverse events of any nature (risk ratio (RR) 2.10, 95% CI 1.27 to 3.47; number needed to treat for an additional harmful outcome (NNTH) 4.6, 95% CI 2.4 to 168.0; 4 trials, n = 181).  There was moderate-certainty evidence that lidocaine local anaesthetic sympathetic blockade probably does not reduce pain intensity compared with placebo, and low-certainty evidence that it may not reduce pain intensity compared with ultrasound of the stellate ganglion. No effect size was reported for either comparison. There was low-certainty evidence that topical dimethyl sulfoxide may not reduce pain intensity compared with oral N-acetylcysteine, but no effect size was reported. There was low-certainty evidence that continuous bupivacaine brachial plexus block may reduce pain intensity compared with continuous bupivacaine stellate ganglion block, but no effect size was reported. For a wide range of other commonly used interventions, the certainty in the evidence was very low and provides insufficient evidence to either support or refute their use. Comparisons with low- and very low-certainty evidence should be treated with substantial caution. We did not identify any RCT evidence for routinely used pharmacological interventions for CRPS such as tricyclic antidepressants or opioids. AUTHORS' CONCLUSIONS: Despite a considerable increase in included evidence compared with the previous version of this overview, we identified no high-certainty evidence for the effectiveness of any therapy for CRPS. Until larger, high-quality trials are undertaken, formulating an evidence-based approach to managing CRPS will remain difficult. Current non-Cochrane systematic reviews of interventions for CRPS are of low methodological quality and should not be relied upon to provide an accurate and comprehensive summary of the evidence.

Relative and absolute reliability of somatosensory evoked potentials in response to non-noxious electrical stimulation of the paraspinal muscles in healthy participants at an interval of 3-months.

BACKGROUND: Somatosensory evoked potentials (SEPs) are used extensively to quantify cortical activity in response to noxious and/or non-noxious sensory stimuli. However, data demonstrating the reliability of SEP measures in response to non-noxious stimulation over time are scarce. AIM: We investigated the relative and absolute reliability, and the smallest detectable change at 95% confidence (SDC95) for SEPs evoked by non-noxious electrical stimulation of the paraspinal muscles in thirty-nine healthy participants at a 3-month interval. METHODS: SEPs were evoked at an intensity three-times that of each participant's perceptual threshold and recorded from a single electrode placed over the primary somatosensory cortex (S1). RESULTS: Our analyses reveal that i) latency, as a measure of activity onset, has poor relative reliability but good absolute reliability; ii) area, as a measure of cortical activity, has good relative and absolute reliability (except for the N150 component) and iii) perceptual threshold and stimulation intensity was not reliable over time. CONCLUSION: These findings suggest that the area of the N80 and P260 SEP components, and the area of the N80-N150-P260 SEP complex, can be utilised in future studies as reliable markers of cortical activity.

Targeting neurotrophic factors for low back pain and sciatica: a systematic review and meta-analysis.

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.

The analgesic effect of electroencephalographic neurofeedback for people with chronic pain: A systematic review and meta-analysis.

BACKGROUND: Electroencephalographic (EEG) neurofeedback has been utilized to regulate abnormal brain activity associated with chronic pain. METHODS: In this systematic review, we synthesized the evidence from randomized controlled trials (RCTs) to evaluate the effect of EEG neurofeedback on chronic pain using random effects meta-analyses. Additionally, we performed a narrative review to explore the results of non-randomized studies. The quality of included studies was assessed using Cochrane risk of bias tools, and the GRADE system was used to rate the certainty of evidence. RESULTS: Ten RCTs and 13 non-randomized studies were included. The primary meta-analysis on nine eligible RCTs indicated that although there is low confidence, EEG neurofeedback may have a clinically meaningful effect on pain intensity in short-term. Removing the studies with high risk of bias from the primary meta-analysis resulted in moderate confidence that there remained a clinically meaningful effect on pain intensity. We could not draw any conclusion from the findings of non-randomized studies, as they were mostly non-comparative trials or explorative case series. However, the extracted data indicated that the neurofeedback protocols in both RCTs and non-randomized studies mainly involved the conventional EEG neurofeedback approach, which targeted reinforcing either alpha or sensorimotor rhythms and suppressing theta and/or beta bands on one brain region at a time. A posthoc analysis of RCTs utilizing the conventional approach resulted in a clinically meaningful effect estimate for pain intensity. CONCLUSION: Although there is promising evidence on the analgesic effect of EEG neurofeedback, further studies with larger sample sizes and higher quality of evidence are required.

Rescaling pain intensity measures for meta-analyses of analgesic medicines for low back pain appears justified: an empirical examination from randomised trials.

OBJECTIVE: Meta-analyses of analgesic medicines for low back pain often rescale measures of pain intensity to use mean difference (MD) instead of standardised mean difference for pooled estimates. Although this improves clinical interpretability, it is not clear whether this method is justified. Our study evaluated the justification for this method. METHODS: We identified randomised clinical trials of analgesic medicines for adults with low back pain that used two scales with different ranges to measure the same construct of pain intensity. We transformed all data to a 0-100 scale, then compared between-group estimates across pairs of scales with different ranges. RESULTS: Twelve trials were included. Overall, differences in means between pain intensity measures that were rescaled to a common 0-100 scale appeared to be small and randomly distributed. For one study that measured pain intensity on a 0-100 scale and a 0-10 scale; when rescaled to 0-100, the difference in MD between the scales was 0.8 points out of 100. For three studies that measured pain intensity on a 0-10 scale and 0-3 scale; when rescaled to 0-100, the average difference in MD between the scales was 0.2 points out of 100 (range 5.5 points lower to 2.7 points higher). For two studies that measured pain intensity on a 0-100 scale and a 0-3 scale; when rescaled to 0-100, the average difference in MD between the scales was 0.7 points out of 100 (range 6.2 points lower to 12.1 points higher). Finally, for six studies that measured pain intensity on a 0-100 scale and a 0-4 scale; when rescaled to 0-100, the average difference in MD between the scales was 0.7 points (range 5.4 points lower to 8.3 points higher). CONCLUSION: Rescaling pain intensity measures may be justified in meta-analyses of analgesic medicines for low back pain. Systematic reviewers may consider this method to improve clinical interpretability and enable more data to be included. STUDY REGISTRATION/DATA AVAILABILITY: Open Science Framework (osf.io/8rq7f).

Post-fracture serum cytokine levels are not associated with a later diagnosis of complex regional pain syndrome: a case-control study nested in a prospective cohort study.

BACKGROUND: Complex Regional Pain Syndrome (CRPS) is a disabling pain disorder that is most common after a distal limb fracture. While the acute systemic immune response to the injury is thought to play a role in the development of CRPS, this hypothesis has never been tested directly. Thus, we evaluated whether elevated levels of circulating pro-inflammatory cytokines early after a fracture were associated with the development of CRPS. METHODS: We conducted a case-control study nested within a prospective cohort study. Individuals with wrist and/or hand fractures were recruited from specialist hand units. Baseline clinical data were obtained from participants within 28 days of fracture. CRPS status was determined 16 weeks after the fracture using a two-stage diagnostic process. Cytokine assays were obtained from all cases (defined using the Budapest criteria) and a random sample of those who did not have CRPS at 16 weeks. We calculated odds ratios with 95% confidence intervals to determine the risk of CRPS associated with the expression of each of 25 cytokines. RESULTS: Baseline data were collected for 702 consenting participants, of whom 535 provided blood samples. Follow-up at 16 weeks was 97.2%. 15 (2.2% of the cohort) met the Budapest CRPS criteria and 69 (including those who met the Budapest criteria; 9.8%) met the International Association for the Study of Pain (IASP) CRPS criteria. In all of the primary analyses (using Budapest criteria) and 49/50 secondary analyses (using IASP criteria), 95% confidence intervals for the association between cytokine levels and the risk of subsequently developing CRPS included the null value (OR = 1). However, the confidence intervals were wide. CONCLUSION: There was no evidence that early post-injury expression of systemic cytokines was associated with a CRPS diagnosis 16 weeks after injury. This study does not provide support for the hypothesis that innate immune activation has a determinative role in the development of CRPS.

Development and measurement properties of the AxEL (attitude toward education and advice for low-back-pain) questionnaire.

INTRODUCTION: Clinician time and resources may be underutilised if the treatment they offer does not match patient expectations and attitudes. We developed a questionnaire (AxEL-Q) to guide clinicians toward elements of first-line care that are pertinent to their patients with low back pain. METHODS: We used guidance from the COSMIN consortium to develop the questionnaire and evaluated it in a sample of people with low back pain of any duration. Participants were recruited from the community, were over 18 years and fluent in English. Statements that represented first-line care were identified. Semantic scales were used to measure attitude towards these statements. These items were combined to develop the questionnaire draft. Construct validity was evaluated with exploratory factor analysis and hypotheses testing, comparing to the Back Beliefs Questionnaire and modified Pain Self-Efficacy Questionnaire. Reliability was evaluated and floor and ceiling effects calculated. RESULTS: We recruited 345 participants, and had complete data for analysis for 313 participants. The questionnaire draft was reduced to a 3-Factor questionnaire through exploratory factor analysis. Factor 1 comprised 9 items and evaluated Attitude toward staying active, Factor 2 comprised 4 items and evaluated Attitude toward low back pain being rarely caused by a serious health problem, Factor 3 comprised 4 items and evaluated Attitude toward not needing to know the cause of back pain to manage it effectively. There was a strong inverse association between each factor and the Back Beliefs Questionnaire and a moderate positive association with the modified Pain Self-Efficacy Questionnaire. Each independent factor demonstrated acceptable internal consistency; Cronbach α Factor 1 = 0.92, Factor 2 = 0.91, Factor 3 = 0.90 and adequate interclass correlation coefficients; Factor 1 = 0.71, Factor 2 = 0.73, Factor 3 = 0.79. CONCLUSION: This study demonstrates acceptable construct validity and reliability of the AxEL-Q, providing clinicians with an insight into the likelihood of patients following first-line care at the outset.

Systemic corticosteroids for radicular and non-radicular low back pain.

BACKGROUND: Corticosteroids are medications with anti-inflammatory and immunosuppressant properties. Systemic corticosteroids administered through the oral, intravenous, or intramuscular routes have been used to treat various types of low back pain, including radicular back pain (not due to spinal stenosis), non-radicular back pain, and spinal stenosis. However, there is uncertainty about the benefits and harms of systemic corticosteroids for low back pain. OBJECTIVES: To evaluate the benefits and harms of systemic corticosteroids versus placebo or no corticosteroid for radicular low back pain, non-radicular low back pain, and symptomatic spinal stenosis in adults. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was September 2021. SELECTION CRITERIA: We included randomized and quasi-randomized trials in adults of systematic corticosteroids versus placebo or no corticosteroid. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. The major outcomes were pain, function, need for surgery, serious adverse effect, and presence of hyperglycemia. The minor outcomes were quality of life, successful outcomes, non-serious adverse events, and withdrawal due to adverse events. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: Thirteen trials (1047 participants) met the inclusion criteria. Nine trials included participants with radicular low back pain, two trial with low back pain, and two trials with spinal stenosis. All trials blinded participants to receipt of systemic corticosteroids. Seven trials were at low risk of bias, five at unclear risk, and one at high risk of selection bias. Two trials were at high risk of attrition bias. Doses and duration of systemic corticosteroid therapy varied. Radicular low back pain For radicular low back pain, moderate-certainty evidence indicated that systemic corticosteroids probably slightly decrease pain versus placebo at short-term follow-up (mean difference (MD) 0.56 points better, 95% confidence interval (CI) 1.08 to 0.04 on a 0 to 10 scale) and may slightly increase the likelihood of experiencing improvement in pain at short-term follow-up (risk ratio (RR) 1.21, 95% CI 0.88 to 1.66; absolute effect 5% better (95% CI 5% worse to 15% better). Systemic corticosteroids may not improve function at short-term follow-up (standardized mean difference (SMD) 0.14 better; range 0.49 better to 0.21 worse) and probably increase the likelihood of improvement in function at short-term follow-up (RR 1.52, 95% CI 1.22 to 1.91; absolute effect 19% better, 95% CI 8% better to 30% better). Systemic corticosteroids were associated with greater improvement in function versus placebo at long-term follow-up (MD -7.40, 95% CI -12.55 to -2.25 on the 0 to 100 Oswestry Disability Index) and greater likelihood of functional improvement (RR 1.29, 95% CI 1.06 to 1.56), based on a single trial. There was no difference in likelihood of surgery (RR 1.00, 95% CI 0.68 to 1.47). Evidence indicated that systemic corticosteroids (administered as a single dose or as a short course of therapy) are not associated with increased risk of any adverse event, serious adverse events, withdrawal due to adverse events, or hyperglycemia, but estimates were imprecise as some trials did not report harms, and harms reporting was suboptimal in trials that did provide data. Limitations included variability across trials in interventions (e.g. corticosteroid used, dose and duration of treatment), clinical settings, and participants (e.g. duration of symptoms, methods for diagnosis); limited utility of subgroup analyses due to small numbers of trials; methodologic limitations or suboptimal reporting of methods by some trials; and too few trials to formally assess for publication bias using graphical or statistical tests for small sample effects. Non-radicular low back pain Evidence on systemic corticosteroids versus placebo for non-radicular pain was limited and suggested that systemic corticosteroids may be associated with slightly worse short-term pain but slightly better function. Spinal stenosis For spinal stenosis, limited evidence indicated that systemic corticosteroids are probably no more effective than placebo for short-term pain or function. AUTHORS' CONCLUSIONS: Systemic corticosteroids appear to be slightly effective at improving short-term pain and function in people with radicular low back pain not due to spinal stenosis, and might slightly improve long-term function. The effects of systemic corticosteroids in people with non-radicular low back pain are unclear and systemic corticosteroids are probably ineffective for spinal stenosis. A single dose or short course of systemic corticosteroids for low back pain does not appear to cause serious harms, but evidence is limited.

If exercise is medicine, why don't we know the dose? An overview of systematic reviews assessing reporting quality of exercise interventions in health and disease.

OBJECTIVE: To determine how well exercise interventions are reported in trials in health and disease. DESIGN: Overview of systematic reviews. DATA SOURCES: PubMed, EMBASE, CINAHL, SPORTDiscus and PsycINFO from inception until June 2021. ELIGIBILITY CRITERIA: Reviews of any health condition were included if they primarily assessed quality of exercise intervention reporting using the Consensus on Exercise Reporting Template (CERT) or the Template for Intervention Description and Replication (TIDieR). We assessed review quality using a modified version of A MeaSurement Tool to Assess systematic Reviews. RESULTS: We identified 7804 studies and included 28 systematic reviews. The median (IQR) percentage of CERT and TIDieR items appropriately reported was 24% (19%) and 49% (33%), respectively. TIDieR items 1, Brief name (median=100%, IQR 4) and 2, Why (median=98%, IQR 6), as well as CERT item 4, Supervision and delivery (median=68%, IQR 89), were the best reported. For replication of exercise interventions, TIDieR item 8, When and how much, was moderately well reported (median=62%, IQR 68) although CERT item 8, Description of each exercise to enable replication (median=23%, IQR 44) and item 13, Detailed description of the exercise intervention (median=24%, IQR 66) were poorly reported. Quality of systematic reviews ranged from moderate to critically low quality. CONCLUSION: Exercise interventions are poorly reported across a range of health conditions. If exercise is medicine, then how it is prescribed and delivered is unclear, potentially limiting its translation from research to practice. PROSPERO REGISTRATION NUMBER: CRD42021261285; Open Science Framework: osf.io/my3ec/.

A Systematic Review of the Reporting Quality of Observational Studies That Use Mediation Analyses.

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.

Effect of Graded Sensorimotor Retraining on Pain Intensity in Patients With Chronic Low Back Pain: A Randomized Clinical Trial.

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.

A Guideline for Reporting Mediation Analyses of Randomized Trials and Observational Studies: The AGReMA Statement.

Importance: Mediation analyses of randomized trials and observational studies can generate evidence about the mechanisms by which interventions and exposures may influence health outcomes. Publications of mediation analyses are increasing, but the quality of their reporting is suboptimal. Objective: To develop international, consensus-based guidance for the reporting of mediation analyses of randomized trials and observational studies (A Guideline for Reporting Mediation Analyses; AGReMA). Design, Setting, and Participants: The AGReMA statement was developed using the Enhancing Quality and Transparency of Health Research (EQUATOR) methodological framework for developing reporting guidelines. The guideline development process included (1) an overview of systematic reviews to assess the need for a reporting guideline; (2) review of systematic reviews of relevant evidence on reporting mediation analyses; (3) conducting a Delphi survey with panel members that included methodologists, statisticians, clinical trialists, epidemiologists, psychologists, applied clinical researchers, clinicians, implementation scientists, evidence synthesis experts, representatives from the EQUATOR Network, and journal editors (n = 19; June-November 2019); (4) having a consensus meeting (n = 15; April 28-29, 2020); and (5) conducting a 4-week external review and pilot test that included methodologists and potential users of AGReMA (n = 21; November 2020). Results: A previously reported overview of 54 systematic reviews of mediation studies demonstrated the need for a reporting guideline. Thirty-three potential reporting items were identified from 3 systematic reviews of mediation studies. Over 3 rounds, the Delphi panelists ranked the importance of these items, provided 60 qualitative comments for item refinement and prioritization, and suggested new items for consideration. All items were reviewed during a 2-day consensus meeting and participants agreed on a 25-item AGReMA statement for studies in which mediation analyses are the primary focus and a 9-item short-form AGReMA statement for studies in which mediation analyses are a secondary focus. These checklists were externally reviewed and pilot tested by 21 expert methodologists and potential users, which led to minor adjustments and consolidation of the checklists. Conclusions and Relevance: The AGReMA statement provides recommendations for reporting primary and secondary mediation analyses of randomized trials and observational studies. Improved reporting of studies that use mediation analyses could facilitate peer review and help produce publications that are complete, accurate, transparent, and reproducible.

Fine-Grained Mapping of Cortical Somatotopies in Chronic Complex Regional Pain Syndrome.

It has long been thought that severe chronic pain conditions, such as complex regional pain syndrome (CRPS), are not only associated with, but even maintained by a reorganization of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations in CRPS patients, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used fMRI to characterize the S1 representation of the affected and unaffected hand in humans (of either sex) with unilateral CRPS. The cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable with those of both the unaffected hand and healthy controls. We found no differential relation between affected versus unaffected hand map measures and clinical measures (pain severity, upper limb disability, disease duration). Thus, if any map reorganization occurs, it does not appear to be directly related to pain and disease severity. These findings compel us to reconsider the cortical mechanisms underlying CRPS and the rationale for interventions that aim to "restore" somatotopic representations to treat pain.SIGNIFICANCE STATEMENT This study shows that the spatial map of the fingers in somatosensory cortex is largely preserved in chronic complex regional pain syndrome (CRPS). These findings challenge the treatment rationale for restoring somatotopic representations in complex regional pain syndrome patients.

Development of A Guideline for Reporting Mediation Analyses (AGReMA).

BACKGROUND: There are a growing number of studies using mediation analysis to understand the mechanisms of health interventions and exposures. Recent work has shown that the reporting of these studies is heterogenous and incomplete. This problem stifles clinical application, reproducibility, and evidence synthesis. This paper describes the processes and methods that will be used to develop a guideline for reporting studies of mediation analyses (AGReMA). METHODS/DESIGN: AGReMA will be developed over five overlapping stages. Stage one will comprise a systematic review to examine relevant evidence on the quality of reporting in published studies that use mediation analysis. In the second stage we will consult a group of methodologists and applied researchers by using a Delphi process to identify items that should be considered for inclusion in AGReMA. The third stage will involve a consensus meeting to consolidate and prioritise key items to be included in AGReMA. The fourth stage will involve the production of AGReMA and an accompanying explanation and elaboration document. In the final stage we will disseminate the AGReMA statement via journals, conferences, and professional meetings across multiple disciplines. DISCUSSION: The development and implementation of AGReMA will improve the standardization, transparency, and completeness in the reporting of studies that use mediation analysis to understand the mechanisms of health interventions and exposures.

Comparative effectiveness of physical exercise interventions for chronic non-specific neck pain: a systematic review with network meta-analysis of 40 randomised controlled trials.

OBJECTIVE: To compare the effectiveness of different physical exercise interventions for chronic non-specific neck pain. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Electronic databases: AMED, CINAHL, Cochrane Central Register of Controlled Trials, Embase, MEDLINE, Physiotherapy Evidence Database, PsycINFO, Scopus and SPORTDiscus. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) describing the effects of any physical exercise intervention in adults with chronic non-specific neck pain. RESULTS: The search returned 6549 records, 40 studies were included. Two networks of pairwise comparisons were constructed, one for pain intensity (n=38 RCTs, n=3151 participants) and one for disability (n=29 RCTs, n=2336 participants), and direct and indirect evidence was obtained. Compared with no treatment, three exercise interventions were found to be effective for pain and disability: motor control (Hedges' g, pain -1.32, 95% CI: -1.99 to -0.65; disability -0.87, 95% CI: -1.45 o -0.29), yoga/Pilates/Tai Chi/Qigong (pain -1.25, 95% CI: -1.85 to -0.65; disability -1.16, 95% CI: -1.75 to -0.57) and strengthening (pain -1.21, 95% CI: -1.63 to -0.78; disability -0.75, 95% CI: -1.28 to -0.22). Other interventions, including range of motion (pain -0.98 CI: -2.51 to 0.56), balance (pain -0.38, 95% CI: -2.10 to 1.33) and multimodal (three or more exercises types combined) (pain -0.08, 95% CI: -1.70 to 1.53) exercises showed uncertain or negligible effects. The quality of evidence was very low according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. CONCLUSION: There is not one superior type of physical exercise for people with chronic non-specific neck pain. Rather, there is very low quality evidence that motor control, yoga/Pilates/Tai Chi/Qigong and strengthening exercises are equally effective. These findings may assist clinicians to select exercises for people with chronic non-specific neck pain. PROSPERO REGISTRATION NUMBER: CRD42019126523.

Causal mechanisms of a healthy lifestyle intervention for patients with musculoskeletal pain who are overweight or obese.

PURPOSE: To assess the causal mechanisms of a healthy lifestyle intervention for patients with chronic low back pain and knee osteoarthritis, who are overweight or obese. METHODS: We conducted causal mediation analyses of aggregated data from two randomized controlled trials (RCTs); which included 160 patients with chronic low back pain, and 120 patients with knee osteoarthritis. The intervention consisted of brief advice and referral to a six-month telephone-based healthy lifestyle coaching service. We used causal mediation to estimate the indirect, direct and path-specific effects of hypothesized mediators including: self-reported weight, diet, physical activity, and pain beliefs. Outcomes were pain intensity, disability, and quality of life (QoL). RESULTS: The intervention did not reduce weight, improve diet or physical activity or change pain beliefs, and these mediators were not associated with the outcomes. Sensitivity analyses showed that our estimates were robust to the possible effects of unknown and unmeasured confounding. CONCLUSIONS: Our findings show that the intervention did not cause a meaningful change in the hypothesized mediators, and these mediators were not associated with patient-reported outcomes.

Musculoskeletal conditions may increase the risk of chronic disease: a systematic review and meta-analysis of cohort studies.

BACKGROUND: Chronic diseases and musculoskeletal conditions have a significant global burden and frequently co-occur. Musculoskeletal conditions may contribute to the development of chronic disease; however, this has not been systematically synthesised. We aimed to investigate whether the most common musculoskeletal conditions, namely neck or back pain or osteoarthritis of the knee or hip, contribute to the development of chronic disease. METHODS: We searched CINAHL, Embase, Medline, Medline in Process, PsycINFO, Scopus and Web of Science to February 8, 2018, for cohort studies reporting adjusted estimates of the association between baseline musculoskeletal conditions (neck or back pain or osteoarthritis of the knee or hip) and subsequent diagnosis of a chronic disease (cardiovascular disease, cancer, diabetes, chronic respiratory disease or obesity). Two independent reviewers performed data extraction and assessed study quality. Adjusted hazard ratios were pooled using the generic inverse variance method in random effect models, regardless of the type of musculoskeletal condition or chronic disease. PROSPERO: CRD42016039519. RESULTS: There were 13 cohort studies following 3,086,612 people. In the primary meta-analysis of adjusted estimates, osteoarthritis (n = 8 studies) and back pain (n = 2) were the exposures and cardiovascular disease (n = 8), cancer (n = 1) and diabetes (n = 1) were the outcomes. Pooled adjusted estimates from these 10 studies showed that people with a musculoskeletal condition have a 17% increase in the rate of developing a chronic disease compared to people without (hazard ratio 1.17, 95% confidence interval 1.13-1.22; I2 52%, total n = 2,686,113 people). CONCLUSIONS: This meta-analysis found that musculoskeletal conditions may increase the risk of chronic disease. In particular, osteoarthritis appears to increase the risk of developing cardiovascular disease. Prevention and early treatment of musculoskeletal conditions and targeting associated chronic disease risk factors in people with long standing musculoskeletal conditions may play a role in preventing other chronic diseases. However, a greater understanding about why musculoskeletal conditions may increase the risk of chronic disease is needed.