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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
1
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.
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
Department of Pain Management and Research, Oslo University Hospital and Faculty of Medicine, University of Oslo,
Oslo, Norway
Percentage spontaneous pain intensity reduction (sub-study 1)
Measured on an 11-point numerical rating scale (0 %= no pain reduction; 100 % = complete pain reduction).
Time frame: 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.
Time frame: Average of usual pain scores one week before each treatment (baseline week) and 1 week after each treatment
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)
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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.
Time frame: 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)
Time frame: 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)
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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).
Time frame: 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)
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 3 weeks after the end of each stimulation period
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