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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. Trial Registration Open Science Framework; https://osf.io/b8adn/ International Registered Report Identifier (IRRID) DERR1-10.2196/22905