Mechanisms and Treatment of Post-amputation Neuropathic Pain

Study Overview
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Brief Summary
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Phantom and residual limb pain are types of peripheral neuropathic pain that are difficult to treat and where the underlying mechanisms are still not fully understood. Repetitive transcranial magnetic stimulation (rTMS) of the motor cortex is an increasingly studied technique for the treatment of neuropathic pain and has shown modest effects in pain intensity reduction for the treatment of neuropathic pain. Newer rTMS coils provide the opportunity to stimulate larger brain areas, which could provide a better treatment option compared to conventional coils. The aims of this study are to investigate whether the peripheral nervous system is a necessary driver of phantom limb pain and/or residual limb pain in patients with lower limb amputation using spinal anaesthesia, and to assess the analgesic efficacy of deep H-coil rTMS compared to sham stimulation in the same patients.

Official Title
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Dependency of the Peripheral Nervous System as a Driver for Post-amputation Pain and Therapeutic Effects of Deep Repetitive Transcranial Magnetic Stimulation in a Randomized Double-blind Sham-controlled Study

Conditions
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Neuropathic Pain, Phantom Limb Pain, Amputation

Intervention / Treatment
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* Drug: Spinal anaesthesia (sub-study 1)
* Device: Repetitive transcranial magnetic stimulation (sub-study 2)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-80 years of age Unilateral or bilateral lower limb amputation resulting in residual limb pain and/or phantom pain, fulfilling the criteria for definite neuropathic pain 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 the study Patients who can be followed for the whole duration of the study Minimum 4/10 pain intensity at the time of spinal anaesthesia for sub-study 1 Exclusion Criteria: 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 Contraindications to spinal anaesthetic block (e.g. use of prescribed or non-prescribed medication that can increase risk of bleeding such as anticoagulants, non-steroidal anti-inflammatory drugs and acetylsalicylic acid) 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) Other pain conditions more severe than phantom and residual limb 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: 80 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: All included patients participate in sub-study 1 and 2. Sub-study 1 is an observational study where patients undergo a spinal anaesthesia in an open label manner. In sub-study 2, patients are once randomly assigned in a 1:1 ratio to one of two counterbalanced arms: either they first receive active rTMS, and then after a 9 week washout period, sham rTMS, or they first receive sham rTMS, and then after 9 weeks of washout, active rTMS. Thus, patients undergo stimulation with deep rTMS in a double blinded randomised controlled trial with a 2 x 2 cross-over design, receiving both active and placebo stimulation
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Active and then sham 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. 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. | Drug: Spinal anaesthesia (sub-study 1)<br>* We will conduct two sub-studies on the same patient group. Sub-study 1 is an observational study where patients with phantom and/or residual limb pain after lower limb amputation will be given spinal anaesthesia with 1% Chloroprocaine in an open label manner to investigate whether the peripheral nervous system is a necessary driver of their pain.<br>Device: Repetitive transcranial magnetic stimulation (sub-study 2)<br>* After sub-study 1, the same patients will enter sub-study 2 where they are randomly assigned to receive either first active rTMS (10 days over 2 weeks), and then after a 9 week washout period, sham rTMS (10 days over 2 weeks), or they first receive sham rTMS, and then after 9 weeks of washout, active rTMS. Thus, patients undergo stimulation with deep rTMS in a double blinded randomised controlled trial with a 2 x 2 cross-over design, receiving both active and placebo stimulation<br>|
| Other: Sham and then active 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.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. | Drug: Spinal anaesthesia (sub-study 1)<br>* We will conduct two sub-studies on the same patient group. Sub-study 1 is an observational study where patients with phantom and/or residual limb pain after lower limb amputation will be given spinal anaesthesia with 1% Chloroprocaine in an open label manner to investigate whether the peripheral nervous system is a necessary driver of their pain.<br>Device: Repetitive transcranial magnetic stimulation (sub-study 2)<br>* After sub-study 1, the same patients will enter sub-study 2 where they are randomly assigned to receive either first active rTMS (10 days over 2 weeks), and then after a 9 week washout period, sham rTMS (10 days over 2 weeks), or they first receive sham rTMS, and then after 9 weeks of washout, active rTMS. Thus, patients undergo stimulation with deep rTMS in a double blinded randomised controlled trial with a 2 x 2 cross-over design, receiving both active and placebo stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage spontaneous pain intensity reduction (sub-study 1) | Measured on an 11-point numerical rating scale (0 %= no pain reduction; 100 % = complete pain reduction). | Maximum reduction during a time interval from 5-60 minutes after spinal anaesthesia | 
| Change in usual pain intensity over the past 24 hours from baseline to 1 week after each treatment (sub-study 2 | Usual pain intensity over the past 24 hours is measured on a 11-point numerical rating scale (0 = no pain, 10 = worst pain intensity imaginable of the current pain condition) every day in a diary at the same hour (end of the day). Analgesic efficacy of active and sham treatment is considered the decrease in usual pain intensity scores between the average of each baseline week (one week before treatment) and average of 1 week after last stimulation of each treatment. | Average of usual pain scores one week before each treatment (baseline week) and 1 week after each treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intensity of brush induced allodynia (sub-study 1) | Maximal pain intensity after 3 brush strokes (SOMEDIC brush) to the area of maximal pain with 2 seconds intervals and 3 cm brush strokes lasting 1 second on a 0-10 numerical rating scale (0 = no pain, 10 = worst pain imaginable) | Measured before, 5 minutes and 30 minutes after spinal anaesthesia | 
| Intensity of pressure induced allodynia (sub-study 1) | Maximal pain intensity after 3 presses using an algometer (10 kPa) to the area of maximal pain with 2 seconds intervals lasting 10 seconds on a 0-10 numerical rating scale (0 = no pain, 10 = worst pain imaginable) | Measured before, 5 minutes and 30 minutes after spinal anaesthesia | 
| Pin-prick sensitivity (sub-study 1) | Compared to contralateral area, sensitivity is measured with a weighted needle (512 mN) on a 0-10 numerical rating scale where 5 is normal sensation, 0 is no sensation and 10 is maximal painful/intense sensation | Measured before, 5 minutes and 30 minutes after spinal anaesthesia | 
| Spontaneous pain intensity right now (sub-study 1) | Measured on a 0-10 numerical rating scale where 0 indicates no pain and 10 indicates worst pain imaginable | Measured before, and 5, 10, 15, 20, 25, 30, 60, 90 and 120 minutes after spinal anaesthesia | 
| Usual pain intensity over the past 24 hours (sub-study 2) | Measured every day in a diary at the same hour (end of the day) on an 11-point numerical rating scale (0 = no pain, 10 = worst pain intensity imaginable of the current pain condition) | Analgesic efficacy of active and sham treatment is measured as the decrease in pain intensity scores between baseline values (one week before treatment) and 3 weeks after the last stimulation. | 
| Pain intensity (sub-study 2) | Pain intensity right now, maximum and minimum pain intensity over the last 24 hours, rated on a numerical rating scale from 0 (no pain) to 10 (pain as bad as you can imagine) | Before, 1 week and 3 weeks after the end of each stimulation period | 
| Pain unpleasantness (sub-study 2) | Pain unpleasantness right now, maximum, minimum, and usual pain unpleasantness during the last 24 hours, rated in a numerical rating scale from 0 (no pain/unpleasantness) to 10 (unpleasantness as bad as you can imagine) | Before, 1 week and 3 weeks after the end of each stimulation period | 
| Pain diary of pain duration, paroxysms and pain interference on sleep (sub-study 2) | Pain duration (percentage wakefulness in pain on an 11-point numerical rating scale; 0% = pain and 100 % = pain all the time), number, duration and usual intensity of pain paroxysms (11-point numerical rating scale; 0 = no pain and 10 = pain as bad as you can imagine), and pain interference on sleep (11-point numerical rating scale; 0 = no interference on sleep, 10 = pain interference on sleep as bad as you can imagine) | Every day 1 week before each stimulation period and up to three weeks after | 
| Proportion of responders (sub-study 2) | 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. | Before,1 week and 3 weeks after the end of each stimulation period | 
| Percentage pain intensity reduction (sub-study 2) | Percentage pain intensity reduction on an 11-point numerical rating scale (0 %= no pain reduction; 100% complete pain reduction) | Before,1 week and 3 weeks after the end of each stimulation period | 
| Pain interference (sub-study 2) | 7 items for pain interference on physical and psychological function from the Brief Pain Inventory rated from 0 (does not interfere), to 10 (complete interference) | Before,1 week and 3 weeks after the end of each stimulation period | 
| Neuropathic Pain Symptom Inventory (sub-study 2) | Measures mean intensity of 10 neuropathic symptoms during the last 24 hours on 11-point (0-10) numerical scales. | Before,1 week and 3 weeks after the end of each stimulation period | 
| Short form McGill Pain questionnaire (sub-study 2) | The sensory and affective score of the short form McGill Pain questionnaire which consists of 15 items measured on a 4 point scale. | Before,1 week and 3 weeks after the end of each stimulation period | 
| Hospital Anxiety and Depression Scale (sub-study 2) | The Hospital Anxiety and Depression Scale includes 14 items scored as anxiety and depression scores, 7 items assessing depression and 7 anxiety | Before,1 week and 3 weeks after the end of each stimulation period | 
| Pain Catastrophizing Scale (sub-study 2) | 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). | Before,1 week and 3 weeks after the end of each stimulation period | 
| Patient Global Impression of Change (sub-study 2) | Consists of 7 items to evaluate the subjective improvement or deterioration (from very much improved to very much deteriorated) | Before,1 week and 3 weeks after the end of each stimulation period | 
| Insomnia Severity Index (sub-study 2) | Consists of self-rated questions which maps sleep difficulties specific to insomnia on a 5 point Likert scale | Before,1 week and 3 weeks after the end of each stimulation period | 
| Patient-Specific Functional Scale (sub-study 2) | 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) | Before,1 week and 3 weeks after the end of each stimulation period | 
| Executive functioning using the CANTAB battery | Composite score and individual scores of the paired associates learning test, stop signal task, spatial working memory test and the multitasking test | Before,1 week and 3 weeks after the end of each stimulation period | 
| Side-effects (sub-study 2) | 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, before and after all other rTMS sessions, and 1 week and 3 weeks after each stimulation period | 
| Blinding (sub-study 2) | 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, spinal anaesthesia