rTMS and Facet Joint Steroid Injection in Chronic Back Pain
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: active repetitive transcranial magnetic stimulation + facet joint injection Active transcranial stimulation will be delivered for a total of 11 sessions. Each session will consist of 40 trains of 5s delivered at 10 Hz, at an intensity of 95% of the resting motor threshold for the first dorsal interosseous muscle and an intertrain interval of 25s (total of 2000 stimulations in a 20-minute session). The facet joint injection will be given 1 week before rTMS begins. A dose of 0.5mL of 40mg/mL triamcinolone and 0.5mL of 2% lidocaine will be given per joint via spinal needle. The treatment team will determine how many joints will be injected based on their standard clinical assessment. Usually, about 2-4 joints are injected depending on a person's pain presentation. Standard practice is to place the needle in the region of the facet joint opening, resulting in a peri- +/- intra-articular infusion of the injectate. This project will utilize this standard clinical practice without modification. |
Device: repetitive transcranial magnetic stimulation
60 minutes after administration of the lumbar FJI, participants will attend their first rTMS session. rTMS will be delivered using a biphasic stimulator (DuoMag) and a figure-of-eight coil to the corticomotor representation of the first dorsal interosseous muscle contralateral to the side of worst LBP. Recording electrodes will be positioned in a belly-tendon montage over the FDI for electromyography recording. 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).
Other Names:
Drug: Facet Joint Injection
The facet joint injection will be given 1 week ahead of active rTMS and sham rTMS commencement. A dose of 0.5mL of 40mg/mL triamcinolone and 0.5mL of 2% lidocaine will be given per joint via spinal needle. The treatment team will determine how many joints will be injected based on their standard clinical assessment. Usually, about 2-4 joints are injected depending on a person's pain presentation. Standard practice is to place the needle in the region of the facet joint opening, resulting in a peri- +/- intra-articular infusion of the injectate. This project will utilize this standard clinical practice without modification.
Other Names:
|
| Sham Comparator: sham repetitive transcranial magnetic stimulation + facet joint injection The sham repetitive transcranial magnetic stimulation coil 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. The facet joint injection will be given 1 week before sham rTMS begins and will also follow the same protocol as the active rTMS group. |
Device: sham repetitive transcranial magnetic stimulation
Sham intervention will follow same protocol as active rTMS using a sham coil that does not deliver actual magnetic stimulation.
Other Names:
Drug: Facet Joint Injection
The facet joint injection will be given 1 week ahead of active rTMS and sham rTMS commencement. A dose of 0.5mL of 40mg/mL triamcinolone and 0.5mL of 2% lidocaine will be given per joint via spinal needle. The treatment team will determine how many joints will be injected based on their standard clinical assessment. Usually, about 2-4 joints are injected depending on a person's pain presentation. Standard practice is to place the needle in the region of the facet joint opening, resulting in a peri- +/- intra-articular infusion of the injectate. This project will utilize this standard clinical practice without modification.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Measures of feasibility and tolerability [Through study completion, an average of 24 weeks]
Data for feasibility, tolerability, and safety will be analyzed using descriptive statistics. Feasibility and tolerability will be measured as (1) the time taken to complete the recruitment of 40 participants, (2) the number of sessions attended by each participant, (3) the number of dropouts in each group, (4) the proportion of participants recruited from the total number screened, and (5) the willingness of each participant to undergo therapy on an 11-point numerical rating scale with 'not at all willing' at 0 and 'very willing' at 10 (measured at baseline).
- Measures for safety [Through study completion, an average of 24 weeks]
Safety will be presented as any adverse reaction reported on verbal questioning at each session. The assessor will record a description of any adverse reactions along with the severity, duration and how the adverse reaction was managed. The number of participants reporting adverse reactions, and the duration and severity of the adverse reactions will be reported.
Secondary Outcome Measures
- Pain Numeric Rating Scale [Weeks 1 through 24]
Pain severity will be assessed at baseline and weekly until week 24 using the 11-point Pain Numeric Rating Scale.
- Brief Pain Inventory - Short Form (BPI-SF) [Weeks 4, 8, 12, 24]
Pain severity and the impact of pain on the patient's daily functioning will be assessed using the 9-item, Brief Pain Inventory short form at baseline, weeks 4, 8, 12, and 24.
- 12-Item Short Form (SF-12) [Weeks 4, 8, 12, 24]
The 12-item short form (SF-12) will be used to assess the quality of life and will be taken at baseline, weeks 4, 12 and 24.
- Oswestry Disability Index (ODI) [Weeks 4, 8, 12, 24]
Disability will be assessed using the Oswestry Disability Index (ODI) at baseline, weeks 4, 8, 12, and 24. The 12-item short form (SF-12) will be used to assess the quality of life and will be taken at baseline, weeks 4, 12 and 24. Finally, as rTMS has previously been shown to positively affect depression and anxiety symptoms, the Depression Anxiety and Stress Scale 21 (DASS-21) will be used to monitor any potential effects our rTMS treatment has on mood. This will be administered at weeks 4, 12, and 24.
- Global Rating of Change Scale (GRC) [Weeks 4 - 24]
A 15-point GRC, with -7 "a very great deal worse", 0 "about the same", to 7 "a very great deal better", will be administered to assess participants' perception of symptom improvement or worsening in response to treatment. The GRC will be administered in weeks 4, 12 and 24.
- Depression Anxiety and Stress Scale 21 (DASS-21) [Weeks 4, 12, 24]
As rTMS has previously been shown to positively affect depression and anxiety symptoms, the Depression Anxiety and Stress Scale 21 (DASS-21) will be used to monitor any potential effects our rTMS treatment has on mood. This will be administered at weeks 4, 12, and 24.
- Measures of Inflammatory Markers [Weeks 1, 6, 12]
Blood will be drawn at baseline, week 6, and week 12 to explore the association between inflammatory markers and treatment response. Serum concentration of interleukins IL-4 and IL-6 will be quantified using a 32x3 simple plex multianalyte cartridge for the Ella automated immunoassay system (ProteinSimple, San Jose, California). Quantification of serum IL-9 will be performed in triplicate via enzyme-linked immunosorbent assay (ThermoFisher Scientific, Massachusetts, USA). Samples will be prepared and loaded into the cartridge for measurement according to standard instructions provided by the manufacturers.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Pain in the low back region (between the thoracolumbar junction and gluteal fold) of an intensity ≥4 on the pain numerical rating scale in the week prior to their most recent FJI and that has been present for at least 6 months
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Participants must have received at least 2 FJIs within the last 12 months at regular intervals
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Participants taking medication will remain eligible for the study if their pharmacological regimen has remained consistent for the past 3 months and are agreeable to maintain a consistent medication dosage throughout the study period.
Exclusion Criteria:
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Known or suspected serious spinal pathology
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Confirmed fracture or dislocation at the time of the injury
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Had spinal surgery in the past 12 months
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Have history of uncontrolled mental health condition(s)
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Other contraindications to spinal injection, and/or
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Have an inflammatory or autoimmune disease
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Meet any specific rTMS-related exclusion criteria listed on the safety screening questionnaire (S1; Rossi et al., 2008).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Parkwood Institute (Main Building) | London | Ontario | Canada | N6C 0A7 |
Sponsors and Collaborators
- Lawson Health Research Institute
- Western University, Canada
Investigators
- Principal Investigator: Siobhan Schabrun, Lawson Health Research Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- FJIrTMS