Treatment of Peripheral Neuropathic Pain

Study Overview
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Brief Summary
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Peripheral neuropathic pain is a disabling chronic pain condition that is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) to the motor cortex is a treatment method with growing evidence in its ability to alleviate neuropathic pain. This also applies to new deep rTMS coils which permits stimulation of larger cortical areas and with deeper penetration. The aim of this study is to investigate the analgesic efficacy of 5 days of deep rTMS compared to sham stimulation. We will also assess effects of deep rTMS on sleep, psychological fatctors, everyday functioning, and executive functioning.

Official Title
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Deep Repetitive Transcranial Magnetic Stimulation for Peripheral Neuropathic Pain. A Randomized Double-blind Sham-controlled Study.

Conditions
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Neuropathic Pain

Intervention / Treatment
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* Device: repetitive Transcranial Magnetic Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-80 years of age Peripheral neuropathic pain related to postherpetic neuralgia, peripheral nerve injury, limb amputation, polyneuropathy or radiculopathy, fulfilling the criteria for probable or definite neuropathic pain (Finnerup et al. 2016) Usual pain intensity at least 4/10 over the past 24 hrs using the numerical scale of the BPI at screening Daily pain Pain for at least 3 months Stable pharmacological treatment for pain or no pharmaceutical treatment at least 1 month prior to inclusion participation Ability to follow throughout the whole duration of the study Exclusion Criteria: atients with phantom limb pain after limb amputation Any clinically significant or unstable medical or psychiatric disorder Subjects protected by law (guardianship or tutelage measure) History of or current substance abuse (alcohol, drugs) Pending litigation Contraindication to rTMS (past severe head trauma, history of epilepsy or ongoing epilepsy, active cerebral tumour, past neurosurgical intervention, intracranial hypertension, implanted devices not compatible such as cardiac pacemaker and neurostimulator, cochlear implants, pregnancy or lactation. All women of childbearing age will be required to have negative pregnancy test at inclusion and to be using contraception) Pain conditions more severe than peripheral neuropathic pain Inability to understand the protocol or to fill out the forms Other ongoing research protocol or recent past protocol within one month before the inclusion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum 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: Crossover Assignment
Interventional Model Description: Patients undergo stimulation with deep rTMS in a double blinded randomised controlled trial (RCT) with a 2 x 2 cross-over design, receiving both active and placebo stimulation. Patients are randomly assigned in a 1:1 ration to one of two counterbalanced arms: either they first receive active rTMS and then sham rTMS after a 9 week washout period, or the first receive sham rTMS and then active rTMS after 9 weeks of washout.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active and then sham rTMS<br>Deep rTMS is delivered with the Brainsway H7-coil (Brainsway, Jerusalem, Israel) applied via a helmet placed on the head targeting the primary motor cortex of the arm. | Device: repetitive Transcranial Magnetic Stimulation<br>* Deep rTMS is delivered with the Brainsway H7-coil (Brainsway, Jerusalem, Israel) applied via a helmet placed on the head targeting the primary motor cortex of the leg.<br>|
| Sham Comparator: Sham and the active rTMS<br>Sham stimulation is delivered with a sham coil placed in the helmet encasing the active rTMS coil. Sham rTMS sessions will use exactly the same parameters of stimulation as active rTMS. | Device: repetitive Transcranial Magnetic Stimulation<br>* Deep rTMS is delivered with the Brainsway H7-coil (Brainsway, Jerusalem, Israel) applied via a helmet placed on the head targeting the primary motor cortex of the leg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Usual pain intensity over the past 24 hours | Measured every day in a diary at the same hour (end of the day) on an 11-point NRS (0 = no pain, 10 = worst pain intensity imaginable of the current pain condition) | Analgesic efficacy of active and sham treatment is measured as the change in pain intensity scores between baseline values (one week before treatment) and 1 week after the last stimulation. Measurement ends 3 weeks after last stimulation] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Usual pain intensity over the past 24 hours | Measured every day in a diary at the same hour on an 11-point NRS (0 = no pain, 10 = worst pain intensity imaginable of the current pain condition) | Analgesic efficacy of active and sham treatment is measured as the change in pain intensity scores between baseline values and 3 weeks after the last stimulation | 
| Pain intensity over the last 24 hours | Maximum and minimum pain intensity hours, rated from 0 (no pain) to 10 (pain as bad as you can imagine) | Baseline, 1 week and 3 weeks after the end of each stimulation period | 
| Pain unpleasantness during the last 24 hours | Maximum, minimum, and usual pain unpleasantness, rated from 0 (no pain/unpleasantness) to 10 (unpleasantness as bad as you can imagine) | Baseline, 1 week and 3 weeks after the end of each stimulation period | 
| Intensity of dynamic mechanical allodynia | Dynamic mechanical allodynia is assessed using a brush (SOMEDIC). The outcome is the mean pain intensity of 3 brush strokes within 2 seconds intervals. The length of the brush stroke is 3 cm, measured on an 11-point NRS (0 = no pain, 10 = worst pain intensity imaginable), disregarding the spontaneous ongoing pain. | Baseline, 1 week and 3 weeks after the end of each stimulation period | 
| Intensity of static mechanical allodynia | Static mechanical allodynia is measured with a stimulus lightly indenting the skin for 10 seconds. The outcome is the mean pain intensity of three presses, measured on an 11-point NRS (0 = no pain, 10 = worst pain intensity imaginable), disregarding the spontaneous ongoing pain. | Baseline, 1 week and 3 weeks after the end of each stimulation period | 
| Proportion of responders | Proportion of responders with at least 30% and 50% usual pain intensity reduction compared to prestimulation values allowing to calculate Numbers Needed to Treat for 30 % and 50 % pain relief. | Baseline,1 week and 3 weeks after the end of each stimulation period] | 
| Percentage pain intensity reduction | Percentage pain intensity reduction on an 11-point NRS (0 %= no pain reduction; 100% complete pain reduction) | Baseline,1 week and 3 weeks after the end of each stimulation period | 
| Hospital Anxiety and Depression Scale | The Hospital Anxiety and Depression Scale includes 14 items scored as anxiety and depression scores, 7 items assessing depression and 7 anxiety | Baseline,1 week and 3 weeks after the end of each stimulation period | 
| Pain Catastrophizing Scale | Consists of 13 items describing the occurrence of thoughts and feelings that individuals may experience when in pain rated from 0 (not at all) to 4 (all the time) | Baseline,1 week and 3 weeks after the end of each stimulation period | 
| Patient Global Impression of Change | Consists of 7 items to evaluate the subjective improvement or deterioration (from very much improved to very much deteriorated) | Baseline,1 week and 3 weeks after the end of each stimulation period | 
| Insomnia Severity Index | Consists of self-rated questions which maps sleep difficulties specific to insomnia on a 5 point Likert scale | Baseline,1 week and 3 weeks after the end of each stimulation period | 
| Patient-Specific Functional Scale | The Patient-Specific Functional Scale is a numeric rating scale that measures individually chosen functions that are inhibited by the pain. Patients rate from 0 (unable to perform activity) to 10 (able to perform activity) | Baseline,1 week and 3 weeks after the end of each stimulation period | 
| Executive functioning using the CANTAB battery | Composite score and individual analyses of the paired associates learning test, stop signal task, spatial working memory test and the multitasking test weeks after the end of each stimulation period | Baseline,1 week and 3 weeks after the end of each stimulation period | 
| Side-effects | Side effects using a specific side effects questionnaire specifically designed for assessment of safety in rTMS studies | Immediately after the first rTMS session for both stimulation periods and 1 week and 3 weeks after each stimulation period | 
| Blinding | Blinding questionnaire | 3 weeks after the end of each stimulation period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Repetitive Transcranial Magnetic Stimulation