Emotion regulation skills-focused interventions for chronic pain: A systematic review and meta-analysis.

OBJECTIVES: To investigate the effect of emotion regulation skills-focused (ERSF) interventions to reduce pain intensity and improve psychological outcomes for people with chronic pain and to narratively report on safety and intervention compliance. METHODS: Six databases and four registries were searched for randomized controlled trials (RCTs) up to 29 April 2022. Risk of bias was evaluated using the Cochrane RoB 2.0 tool, and certainty of evidence was assessed according to the Grading, Assessment, Development and Evaluation (GRADE). Meta-analyses for eight studies (902 participants) assessed pain intensity (primary outcome), emotion regulation, affect, symptoms of depression and anxiety, and pain interference (secondary outcomes), at two time points when available, post-intervention (closest to intervention end) and follow-up (the first measurement after the post-intervention assessment). RESULTS: Compared to TAU, pain intensity improved post-intervention (weighted mean difference [WMD] = -10.86; 95% confidence interval [CI] [-17.55, -2.56]) and at follow-up (WMD = -11.38; 95% CI [-13.55, -9.21]). Emotion regulation improved post-intervention (standard mean difference [SMD] = 0.57; 95% CI [0.14, 1.01]), and depressive symptoms improved at follow-up (SMD = -0.45; 95% CI [-0.66, -0.24]). Compared to active comparators, anxiety symptoms improved favouring the comparator post-intervention (SMD = 0.10; 95% CI [0.03, 0.18]), and compared to CBT, pain interference improved post-intervention (SMD = -0.37; 95% CI [-0.69, -0.04]). Certainty of evidence ranged from very low to moderate. SIGNIFICANCE: The findings provide evidence that ERSF interventions reduce pain intensity for people with chronic pain compared to usual treatment. These interventions are at least as beneficial to reduce pain intensity as the current gold standard psychological intervention, CBT. However, the limited number of studies and certainty of evidence mean further high-quality RCTs are warranted. Additionally, further research is needed to identify whether ERSF interventions may be more beneficial for specific chronic pain conditions.

A Qualitative Study Identifying Barriers and Enablers to Exercise Adherence in People with Chronic Low Back Pain. "It's a personal journey".

Exercise leads to clinically meaningful pain reductions in people with chronic low back pain and is recommended as a first line treatment. The benefits of exercise for chronic low back pain decrease over time with a lack of long-term exercise adherence as a potential reason for this decreasing effect. We aimed to identify the barriers and enablers to exercise adherence from the perspective of people with chronic low back pain. This qualitative study was underpinned by a constructivist epistemology and used a critical realist ontological perspective. Adults (18-65 years) with chronic low back pain who had exercised since the onset of their back pain were recruited to participate in focus groups and individual interviews. Audio data were transcribed and then analysed in 2 stages 1) inductive coding using reflexive thematic analysis, followed by 2) deductive analysis through mapping codes onto the Theoretical Domains Framework. Five enablers and 3 barriers were identified across 6 of the 14 Theoretical Domain Framework domains. Exercise identity and confidence in deciding to self-manage pain were enablers, whereas beliefs about the consequences of exercise, exercise context, and relationships could function as either barriers or enablers. These barriers and enablers were complex and fluid, with participants reporting conflicting barriers and enablers that varied, depending on context. These findings improve our understanding of the barriers and enablers to exercise adherence from the individual perspective of people with chronic low back pain and can be utilised for more effective exercise treatment in this population. PERSPECTIVE: This article presents the barriers and enablers to exercise adherence from the perspective of people with chronic low back pain. These perspectives may aid to individualise and optimise exercise treatment, improve its long-term adherence and therefore its effectiveness for chronic low back pain.

Human lower leg muscles grow asynchronously.

Muscle volume must increase substantially during childhood growth to generate the power required to propel the growing body. One unresolved but fundamental question about childhood muscle growth is whether muscles grow at equal rates; that is, if muscles grow in synchrony with each other. In this study, we used magnetic resonance imaging (MRI) and advances in artificial intelligence methods (deep learning) for medical image segmentation to investigate whether human lower leg muscles grow in synchrony. Muscle volumes were measured in 10 lower leg muscles in 208 typically developing children (eight infants aged less than 3 months and 200 children aged 5 to 15 years). We tested the hypothesis that human lower leg muscles grow synchronously by investigating whether the volume of individual lower leg muscles, expressed as a proportion of total lower leg muscle volume, remains constant with age. There were substantial age-related changes in the relative volume of most muscles in both boys and girls (p < 0.001). This was most evident between birth and five years of age but was still evident after five years. The medial gastrocnemius and soleus muscles, the largest muscles in infancy, grew faster than other muscles in the first five years. The findings demonstrate that muscles in the human lower leg grow asynchronously. This finding may assist early detection of atypical growth and allow targeted muscle-specific interventions to improve the quality of life, particularly for children with neuromotor conditions such as cerebral palsy.

Reporting of Observational Studies Explicitly Aiming to Emulate Randomized Trials: A Systematic Review.

Importance: Observational (nonexperimental) studies that aim to emulate a randomized trial (ie, the target trial) are increasingly informing medical and policy decision-making, but it is unclear how these studies are reported in the literature. Consistent reporting is essential for quality appraisal, evidence synthesis, and translation of evidence to policy and practice. Objective: To assess the reporting of observational studies that explicitly aimed to emulate a target trial. Evidence Review: We searched Medline, Embase, PsycINFO, and Web of Science for observational studies published between March 2012 and October 2022 that explicitly aimed to emulate a target trial of a health or medical intervention. Two reviewers double-screened and -extracted data on study characteristics, key predefined components of the target trial protocol and its emulation (eligibility criteria, treatment strategies, treatment assignment, outcome[s], follow-up, causal contrast[s], and analysis plan), and other items related to the target trial emulation. Findings: A total of 200 studies that explicitly aimed to emulate a target trial were included. These studies included 26 subfields of medicine, and 168 (84%) were published from January 2020 to October 2022. The aim to emulate a target trial was explicit in 70 study titles (35%). Forty-three studies (22%) reported use of a published reporting guideline (eg, Strengthening the Reporting of Observational Studies in Epidemiology). Eighty-five studies (43%) did not describe all key items of how the target trial was emulated and 113 (57%) did not describe the protocol of the target trial and its emulation. Conclusion and Relevance: In this systematic review of 200 studies that explicitly aimed to emulate a target trial, reporting of how the target trial was emulated was inconsistent. A reporting guideline for studies explicitly aiming to emulate a target trial may improve the reporting of the target trial protocols and other aspects of these emulation attempts.

Mechanisms of education and graded sensorimotor retraining in people with chronic low back pain: a mediation analysis.

ABSTRACT: An improved understanding of the biopsychosocial influences that contribute to and maintain pain has promoted the development of new efficacious treatments for chronic low back pain (CLBP). This study aimed to investigate the mechanisms of a new treatment-education and graded sensorimotor retraining-on pain and disability. We conducted a preplanned causal mediation analysis of a randomized clinical trial which allocated 276 participants with CLBP to 12 weekly clinical sessions of education and graded sensorimotor retraining (n = 138) or a sham and attention control (n = 138). Outcomes were pain intensity and disability, both assessed at 18 weeks. Hypothesized mediators included tactile acuity, motor coordination, back self-perception, beliefs about the consequences of back pain, kinesiophobia, pain self-efficacy, and pain catastrophizing, all assessed at the end of treatment (12 weeks). Four of 7 mechanisms (57%) mediated the intervention effect on pain; the largest mediated effects were for beliefs about back pain consequences (-0.96 [-1.47 to -0.64]), pain catastrophizing (-0.49 [-0.61 to -0.24]), and pain self-efficacy (-0.37 [-0.66 to -0.22]). Five of 7 mechanisms (71%) mediated the intervention effect on disability; the largest mediated effects were for beliefs about back pain consequences (-1.66 [-2.62 to -0.87]), pain catastrophizing (-1.06 [-1.79 to -0.53]), and pain self-efficacy (-0.84 [-1.89 to -0.45]). When all 7 mechanisms were considered simultaneously, the joint mediation effect explained most of the intervention effect for both pain and disability. Optimizing interventions to target beliefs about the consequences of back pain, pain catastrophizing, and pain self-efficacy is likely to lead to improved outcomes for people with CLBP.

"My Back is Fit for Movement": A Qualitative Study Alongside a Randomized Controlled Trial for Chronic Low Back Pain.

A new wave of treatments has emerged to target nervous system alterations and maladaptive conceptualizations about pain for chronic low back pain. The acceptability of these treatments is still uncertain. We conducted a qualitative study alongside a randomized controlled trial to identify perceptions of facilitators or barriers to participation in a non-pharmacological intervention that resulted in clinically meaningful reductions across 12 months for disability compared to a sham intervention. We conducted semi-structured interviews with participants from the trial's active arm after they completed the 12-week program. We included a purposeful sample (baseline and clinical characteristics) (n = 20). We used reflexive thematic analysis informed by the Theoretical Framework of Acceptability for health care interventions. We identified positive and negative emotional/cognitive responses associated with treatment acceptability and potential efficacy, including emotional support, cognitive empowerment, readiness for self-management, and acceptance of face-to-face and online components designed to target the brain. These findings suggest the importance of psychoeducation and behavior change techniques to create a positive attitude towards movement and increase the perception of pain control; systematic approaches to monitor and target misconceptions about the interventions during treatment; and psychoeducation and behavior change techniques to maintain the improvements after the cessation of formal care. PERSPECTIVE: This article presents the experiences of people with chronic low back pain participating in a new non-pharmacological brain-targeted treatment that includes face-to-face and self-directed approaches. The facilitators and barriers of the interventions could potentially inform adaptations and optimization of treatments designed to target the brain to treat chronic low back pain.

Development of a booster intervention for graded sensorimotor retraining (RESOLVE) in people with persistent low back pain: A nested, randomised, feasibility trial.

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 <3 contacts were necessary to arrange the booster session; there were sufficient willing participants (<15% of sample unwilling to participate); and participants and research clinicians reported a perceived benefit of >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.

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 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.

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.

Efficacy, acceptability, and safety of muscle relaxants for adults with non-specific low back pain: systematic review and meta-analysis.

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/.

Investigating the Mechanisms of Graded Sensorimotor Precision Training in Adults With Chronic Nonspecific Low Back Pain: Protocol for a Causal Mediation Analysis of the RESOLVE Trial.

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.

The mediating effect of pain catastrophizing on pain intensity: The influence of the timing of assessments.

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.

Efficacy, acceptability, and safety of antidepressants for low back pain: a systematic review and meta-analysis.

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 ).

Efficacy and Safety of Medicines Targeting Neurotrophic Factors in the Management of Low Back Pain: Protocol for a Systematic Review and Meta-analysis.

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 RESOLVE Trial for people with chronic low back pain: statistical analysis plan.

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).

Hypnosis Enhances the Effects of Pain Education in Patients With Chronic Nonspecific Low Back Pain: A Randomized Controlled Trial.

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.