Clinical trial NCT04819503: Mechanisms and Treatment of Post-amputation Neuropathic Pain
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Neuropathic Pain
Phantom Limb Pain
Amputation
Keywords: repetitive transcranial magnetic stimulation
spinal anaesthesia
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
First posted: 2021-03-29
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage spontaneous pain intensity reduction (sub-study 1)
timeFrame: Maximum reduction during a time interval from 5-60 minutes after spinal anaesthesia
measure: Change in usual pain intensity over the past 24 hours from baseline to 1 week after each treatment (sub-study 2
timeFrame: Average of usual pain scores one week before each treatment (baseline week) and 1 week after each treatment
Secondary outcomes:
measure: Intensity of brush induced allodynia (sub-study 1)
timeFrame: Measured before, 5 minutes and 30 minutes after spinal anaesthesia
measure: Intensity of pressure induced allodynia (sub-study 1)
timeFrame: Measured before, 5 minutes and 30 minutes after spinal anaesthesia
measure: Pin-prick sensitivity (sub-study 1)
timeFrame: Measured before, 5 minutes and 30 minutes after spinal anaesthesia
measure: Spontaneous pain intensity right now (sub-study 1)
timeFrame: Measured before, and 5, 10, 15, 20, 25, 30, 60, 90 and 120 minutes after spinal anaesthesia
measure: Usual pain intensity over the past 24 hours (sub-study 2)
timeFrame: 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.
measure: Pain intensity (sub-study 2)
timeFrame: Before, 1 week and 3 weeks after the end of each stimulation period
measure: Pain unpleasantness (sub-study 2)
timeFrame: Before, 1 week and 3 weeks after the end of each stimulation period
measure: Pain diary of pain duration, paroxysms and pain interference on sleep (sub-study 2)
timeFrame: Every day 1 week before each stimulation period and up to three weeks after
measure: Proportion of responders (sub-study 2)
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Percentage pain intensity reduction (sub-study 2)
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Pain interference (sub-study 2)
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Neuropathic Pain Symptom Inventory (sub-study 2)
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Short form McGill Pain questionnaire (sub-study 2)
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Hospital Anxiety and Depression Scale (sub-study 2)
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Pain Catastrophizing Scale (sub-study 2)
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Patient Global Impression of Change (sub-study 2)
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Insomnia Severity Index (sub-study 2)
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Patient-Specific Functional Scale (sub-study 2)
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Executive functioning using the CANTAB battery
timeFrame: Before,1 week and 3 weeks after the end of each stimulation period
measure: Side-effects (sub-study 2)
timeFrame: 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
measure: Blinding (sub-study 2)
timeFrame: 3 weeks after the end of each stimulation period
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Department of Pain Management and Research, Oslo University Hospital and Faculty of Medicine, University of Oslo,
Study officials:
affiliation: Oslo University Hospital
name: Audun Stubhaug, DMedSci
role: STUDY_DIRECTOR
References: