Background:~Chronic low back pain (CLBP) is one of the most common chronic pain conditions globally. The pathophysiology of CLBP is complex, and it is thought that both nociceptive and central pain mechanisms may be involved. Facet joint injections (FJI) are a routine therapeutic intervention for patients with CLBP that is recalcitrant to other types of treatment. However, FJI has been shown to have limited long-term efficacy with patients requiring another injection within months to adequately control pain. One option to prolong the analgesic effects of FJI may be to incorporate repetitive transcranial magnetic stimulation (rTMS) as an adjunct therapy. Studies have shown rTMS may be capable of providing long-term pain relief in patients with CLBP. However, the literature on rTMS in patients with CLBP is limited and no study has explored rTMS in patients receiving recurrent FJI for pain control.~In addition, the mechanisms through which rTMS might exert therapeutic effects on CLBP are unclear. Cytokine-mediated neuroinflammation has been shown to have a key role in the initiation and maintenance of chronic pain. Growing evidence suggests that this is in part due to the sensitization of nociceptors following injury via upregulation of pro-inflammatory cytokines, such as interleukin 6 (IL-6). If prolonged or excessive, this sensitization may lead to changes in synaptic plasticity, contributing to chronic pain. Treatment success has been associated with the downregulation of these pro-inflammatory markers, and an upregulation of anti-inflammatory cytokines, such as interleukin 4 (IL-4). Recently, interleukin 9 (IL-9) has also gained attention for its role in pain. Though limited, the available literature on this cytokine has shown it to have a pro-resolution role in chronic pain. However, no study to date has examined these inflammatory markers in association with rTMS treatment success.~Thus, the aims of this study are to determine: (1) trends towards the feasibility, tolerability, safety, and perceived patient response to a combined rTMS and FJI intervention, (2) whether rTMS combined with FJIs (active rTMS group) may have greater benefits for pain and function than FJIs alone (sham rTMS group), and (3) the relationship between serum levels of cytokines IL-4, IL-6, and IL-9 and rTMS/FJI treatment response. The investigators hypothesize that a combined rTMS and FJI intervention be feasible, tolerable, and safe and will have larger and longer-lasting effects on chronic low back pain than a sham rTMS and FJI intervention. Further, it is hypothesized that IL-4 and IL-9 will be upregulated, and IL-6 downregulated, relative to baseline, in response to the active rTMS and FJI intervention but not in response to the sham rTMS and FJI intervention. Serum levels of IL-4 and IL-9 will negatively correlate, and IL-6 positively correlate, with subjective ratings for pain throughout the study in the treatment and control group.~Study Design:~This pilot study is a randomized, participant- and assessor-blind controlled trial of active and sham repetitive transcranial magnetic stimulations (rTMS) in a population of individuals with CLBP, who are receiving recurrent FJIs at three- to six-month intervals through the St Joseph's Pain Clinic. The rTMS intervention will begin 1 hour after FJI and include a 2-week induction phase with active or sham rTMS delivered 3 times each week. The purpose of the induction phase is to strengthen the effects of rTMS at the start of the treatment through multiple sessions in a relatively short period of time. A maintenance phase will follow and in weeks 3, 4, 6, 8, and 12 participants will receive a single active or sham rTMS session. Pain severity will be assessed weekly using an electronic diary from baseline (the week of FJI until week 24). Disability and quality of life will be assessed at baseline, 4, 8, 12, 18 and 24 weeks. Blood will be drawn prior to FJI and in weeks 6 and 12.~Participants:~Forty adults (≥18 years old) with CLBP who are currently receiving recurrent FJIs for control of CLBP at the St. Joseph's Health Centre Pain Clinic in London, Ontario, Canada will be recruited.~Sample Size:~This is a pilot randomized controlled study designed to generate data that can be used to inform a future large-scale trial should the intervention appear feasible, safe and show trends of effectiveness. Thus, the investigators have selected a sample size of 20 individuals per group for a total of 40 participants. A sample size of 40 participants was selected as this is considered achievable within the time frame allocated for the completion of the pilot study according to participant recruitment rates within the pain clinic. The aim is to evaluate key trial parameters, such as recruitment and retention of participants, randomization, the success of blinding, acceptability of the intervention, levels of missing data and preliminary indications of effectiveness, to inform the calculation of a sample size for powering a full trial.~Facet Joint Injections (FJI):~FJI will be given by an interventional pain physician following the standard clinical procedure for the St. Joseph's Health Centre Pain Clinic. The treatment team will determine how many joints will be injected based on their standard clinical assessment.~Repetitive transcranial magnetic stimulation (rTMS):~60 minutes after administration of the lumbar FJI, participants will attend their first rTMS session. rTMS will be delivered to the corticomotor representation of the first dorsal interosseous (FDI) muscle contralateral to the side of worst LBP. The hotspot and resting motor threshold (rMT) of the FDI will be determined and saved using a Brainsight Neuronavigation system to ensure accurate coil repositioning within and between sessions.~The hotspot and rMT will be confirmed and adjusted if needed at each intervention session. Each rTMS session will consist of 40 trains of 5s delivered at 10Hz, at an intensity of 95% of the resting motor threshold for the FDI muscle and an intertrain interval of 25s (total of 2000 stimulations in a 20-minute session). Sham rTMS will be delivered using a sham coil of identical colour, size, and shape as the active rTMS coil. The sham coil uses a magnetic shield that blocks the magnetic field from being delivered to the scalp while producing a similar auditory click during discharge. All other aspects of the rTMS protocol will be identical between the active and sham conditions.~Measures of Inflammatory Molecules:~Blood will be drawn at baseline, week 6, and week 12 to explore the association between inflammatory markers and treatment response. To avoid any interference with cytokine levels, all participants will be asked to fast overnight prior to the blood draw. Fasting includes refraining from food, alcohol, caffeine, and nicotine for 8-12 hours prior to the blood collection.~Confidentiality and Data Security:~All study data will be stored electronically on a password-protected, FireVault-encrypted, laptop in the office of the Principal Investigator. Access to study data and/or medical records will be limited to authorized study personnel only. A master log with identifiers will be stored separately from the study data.~The participant will be able to withdraw at any point during data collection. The data will be unable to be withdrawn once it has been pooled with other participants' data for statistical tests for the purposes of a paper or abstract however these data will be de-identified.~Statistical Analysis:~All statistical analyses will be carried out using the software R. Data for feasibility and safety will be analyzed using descriptive statistics. To determine trends of effectiveness, analyses of pain and disability will be performed according to intention-to-treat and per protocol using analysis of variance (ANOVA) to assess change within groups and the differences between groups over time (pre/post). All data will be assessed for normality using the Shapiro-Wilk test. Normally distributed data will be assessed using 2-way repeated measures of ANOVA with 2 levels for intervention (active rTMS/sham rTMS) and levels for time (0, 4, 8, 12, and 24 weeks) as separate factors. If significant group x time interactions are found, then Bonferroni post hoc tests will be used to determine which means are significantly different from one another. Non-parametric data will be assessed via a Mann-Whitney U test on change scores between groups. The effect size will be determined using partial η2 from planned contrasts. The size of the treatment effects will be used to determine whether it is worthwhile to conduct a full randomized controlled trial in the future. Given the pilot nature of this trial, missing data will not be replaced. Bonferroni post hoc tests will be applied if appropriate. The α will be set at 0.05 for all tests.~Results will be corrected for false discovery rate using Benjamini-Hochberg correction where an adjusted p-value of < 0.05 will be considered significant.~Spearman rank correlation coefficient will be determined to calculate the correlation between the scores obtained from the NPRS questionnaire and serum interleukin levels.
Chronic low back pain (CLBP) is one of the most common chronic pain conditions globally. Facet joint injections are a routine treatment option for patients with CLBP that is recalcitrant to other treatments. However, FJI has been shown to have limited long-term efficacy with patients often requiring another injection within months to adequately control pain. One option to prolong the analgesic effects of FJI is to use a type of noninvasive brain stimulation called repetitive transcranial magnetic stimulation (rTMS). Previous studies have shown rTMS may be capable of providing long-term pain relief in patients with CLBP. However, the literature on rTMS in patients with CLBP is limited and no study has explored rTMS in patients receiving recurrent FJI for pain control.~What is also unclear is the mechanisms through which rTMS might exert therapeutic effects on CLBP. Neuroinflammation has been shown to have a key role in the initiation and maintenance of chronic pain, particularly through the actions of serum pro- and anti-inflammatory proteins.~In this pilot randomized controlled trial study, we'll be investigating if combining rTMS with FJI in CLBP individuals will enhance or prolong the analgesic effects of FJI alone. We'll also be studying the relationship between specific pro- and anti-inflammatory proteins and rTMS/FJI treatment response.~The investigators hypothesize that a combined rTMS and FJI intervention will be feasible, tolerable, and safe and will have larger and longer-lasting effects on CLBP than a sham rTMS and FJI intervention. Further, it is hypothesized that anti-inflammatory proteins, such as IL-4 and IL-9, will be upregulated, and pro-inflammatory proteins, such as IL-6, downregulated, relative to baseline, in response to the active rTMS and FJI intervention but not in response to the sham rTMS and FJI intervention.