Long-term Effects of Repetitive TMS in Chronic Neuropathic Pain in People With SCI

Study Overview
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Brief Summary
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Around 80% of people with spinal cord injury (SCI) develop chronic neuropathic pain (CNP). This is a debilitating condition with major negative impacts on people's quality of life. Many treatment options have been offered (invasive stimulation, drugs) but provide limited effects and many secondary effects. There is a critical need to develop a new generation of therapies. Transcranial magnetic stimulation (TMS) is a non-invasive and painless brain stimulation technique that allows researchers to explore and change brain excitability that has shown promising effects in neuropathic pain. However there is not enough evidence of what are the long lasting effects of the different protocols. In this study, 30 SCI subjects with CNP in their hands will participate in the study. The objective is to evaluate the efficacy of real versus sham repetitive transcranial magnetic stimulation (rTMS) and investigate 1) short and long term effects on pain and 2) the behavioral and neurophysiological qualities of responders and non-responders to this treatment.This will be a randomized sham controlled trial with two groups: real or sham high frequency repetitive TMS protocol (20Hz). The protocol will be done daily for two weeks. Clinical, functional and neurophysiological evaluations will be assessed at baseline, post intervention and at 6-week follow up.

Official Title
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Long-term Effects of Repetitive TMS in Chronic Neuropathic Pain in People With SCI

Conditions
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Spinal Cord Injuries, Neuralgia, Chronic Pain

Intervention / Treatment
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* Device: Transcranial Magnetic Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: presence of chronic neuropathic pain at or below SCI level for at least 6 months following trauma or disease of the spinal cord. cervical lesion. CNP in the upper extremity. pain intensity of at least 4 out of 10 in the numerical rating scale (NRS) in the NPS both screening (baseline) and randomization (pre-evaluation).both screening (baseline) and randomization (pre-evaluation). stable pharmacological treatment for at least 2 weeks prior to the study and throughout the trial. complete or incomplete lesion. Exclusion criteria:

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized double blinded sham controlled study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Real rTMS group<br>Repetitive TMS at 20Hz frequency over the M1 will be performed for five consecutive days for 2 weeks (using 90% of the resting motor threshold/total of 500 pulses). The rTMS will be applied through a figure-8 coil connected to a magnetic stimulator, which provides a biphasic pulse. This protocol was developed in accordance with the guidelines for the safe use of rTMS. | Device: Transcranial Magnetic Stimulation<br>* Transcranial magnetic stimulation (TMS) is a non-invasive and painless brain stimulation technique that allows the brain excitability to change based on Faraday's Law of Electromagnetic induction . Since the presentation of the CNP is usually bilateral, the coil will be targeting the dominant hand abductor pollicis brevis (APB) muscle. If the pain is more intense in one of the arms, that arm will be targeted. This protocol was developed in accordance with the guidelines for the safe use of rTMS.<br>|
| Sham Comparator: Sham group<br>Sham stimulation will be performed for five consecutive days for 2 weeks (using 90% of the resting motor threshold/total of 500 pulses). For the sham stimulation a sham coil will be used. | Device: Transcranial Magnetic Stimulation<br>* Transcranial magnetic stimulation (TMS) is a non-invasive and painless brain stimulation technique that allows the brain excitability to change based on Faraday's Law of Electromagnetic induction . Since the presentation of the CNP is usually bilateral, the coil will be targeting the dominant hand abductor pollicis brevis (APB) muscle. If the pain is more intense in one of the arms, that arm will be targeted. This protocol was developed in accordance with the guidelines for the safe use of rTMS.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropathic Pain Scale (NPS) | This scale was developed to assess both the quantitative and qualitative qualities of NP. It includes 11 items, assessing global pain intensity, unpleasantness, and one item which allows the patient to describe the temporal aspects of their pain and its qualities in their own words. The remaining 8 items assess specific NP qualities: Sharp, Hot, Dull, Cold, Sensitive, Itchy, Deep, and Surface. This is a sensitive tool for measuring changes in neuropathic pain after a therapeutic intervention. Total scale from 0-10, with higher score indicating more pain. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numeric Rating Scale (NRS) | NRS to measure pain sensation, total score from 0-10, higher score indicates more intense pain. | 6 weeks | 
| Short-Form McGill Pain Questionnaire. (SF-MPQ) | The main component of the SF-MPQ consists of 15 descriptors (11 sensory; 4 affective) which are rated on an intensity scale as 0 = none, 1 = mild, 2 = moderate or, 3 = severe. The SF-MPQ can be scored in several ways: a) number of words/descriptors chosen by the patient. Total scale from 0 to 45, with higher score indicating higher the pain experienced. | 6 weeks | 
| Present Pain Intensity (PPI) index | In the PPI index the adjectives/descriptors are ranked according to increasing intensity so each descriptor can be assigned a higher score: 0= no pain, 1=mild, 2=discomforting, 3= distressing, 4= horrible, 5= excruciating. Full range from 0 to 75, with higher score indicating higher intensity pain experienced. | 6 weeks | 
| Visual Analogue Scale (VAS) | The Visual Analogue Scale is the pain rating scale. Full scale from 0 to 10, with higher score indicating more pain. | 6 weeks | 
| The American Spinal Injury Association Impairment Scale (ASIA scale) | Upper extremity motor score (UEMS) will test the clinical motor strength from 0 to 5 of each key muscle using the ASIA scale in both arms. This sum score will range from 0 (paralyzed) to 25 (normal) in each limb (total of 50 bilaterally). Higher score indicates better health outcomes | 6 weeks | 
| Spinal cord independence measure (SCIM III) | Spinal cord independence measure (SCIM III) measures the ability of patients with SCI to perform everyday tasks. SCIM is used for quantitative functional outcome assessment following interventions designed to promote recovery from spinal cord injury and to increase functional achievement; it covers 19 tasks in 16 categories, with a total score range 0-100; all activities of daily living, grouped into four areas of function (subscales): Self-Care (scored 0-20), Respiration and Sphincter Management (0-40), Mobility in Room and Toilet (0-10), and Mobility Indoors and Outdoors (0-30). Higher score indicates better health outcomes. | 6 weeks | 
| Modified Ashworth Scale (MAS) | Modified Ashworth Scale (MAS) will measure changes in spasticity in the upper limbs after the stimulation period. For each upper limb, full Score range from 0 to 4, where lower. scores represent normal muscle tone and higher scores represent spasticity or increased resistance to passive movement. | 6 weeks | 
| Beck Depression Inventory (BDI) | This questionnaire is a 21-item, selfreport rating inventory that measures characteristic attitudes and symptoms of depression. Scoring is from 0 (minimal) to 3 (severe), with total score from 0-63. Higher total scores indicate more severe depressive symptoms. | 6 weeks | 
| Patient's Global Impression of Change (PGIC) | Full scale from 0-7, higher score indicates better health outcomes. he patients will answer the following question: Since beginning treatment at this program, how would you describe the change (if any) in activity limitations, symptoms, emotions, and overall quality of life related to your condition? | 6 weeks | 
| Resting Motor Threshold (RMT) | Using transcranial magnetic stimulation (TMS) and electromyography (EMG) to measure RMT. Motor threshold is considered to reflect membrane-related intrinsic neuronal excitability. | 6 weeks | 
| Recruitment curve (RC) | Using transcranial magnetic stimulation (TMS) and electromyography (EMG) to measure RC. The median amplitude at a given intensity is thought to represent trans-synaptic excitability of the corticospinal pathways. | 6 weeks | 
| Short intracortical inhibition (SICI) | Using transcranial magnetic stimulation (TMS) and electromyography (EMG) to measure SICI. A single pulse TMS stimulus can be inhibited if preceded by a subthreshold conditioning stimulus 3 milliseconds apart. The SICI determines if changes in corticospinal output are related to altered intracortical excitability. | 6 weeks | 
| Silent period (SP): | Using transcranial magnetic stimulation (TMS) and electromyography (EMG) to measure SP. During muscle contraction, the MEP is followed by a period of silent EMG activity. Changes in intracortical inhibition are reflected in altered SP duration. | 6 weeks | 
| Sensory threshold (ST): | Using a constant current electrical stimulator (Digitimer), sensory threshold can be quantified. It is defined as the weakest stimulus that can be detected. | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal Cord Injuries, Neuropathic, Chronic Pain, Transcranial Magnetic Stimulation, Neural Plasticity, Pain