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Mechanisms and Treatment of Post-amputation Neuropathic Pain

Primary Purpose

Neuropathic Pain, Phantom Limb Pain, Amputation

Status

Unknown status

Phase

Not Applicable

Locations

Norway

Study Type

Interventional

Intervention

Spinal anaesthesia (sub-study 1)

Repetitive transcranial magnetic stimulation (sub-study 2)

About this trial

This is an interventional treatment trial for Neuropathic Pain focused on measuring repetitive transcranial magnetic stimulation, spinal anaesthesia

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Department of Pain Management and Research, Oslo University Hospital and Faculty of Medicine, University of Oslo,

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Arm Label

Active and then sham repetitive transcranial magnetic stimulation

Sham and then active repetitive transcranial magnetic stimulation

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Percentage spontaneous pain intensity reduction (sub-study 1)

Measured on an 11-point numerical rating scale (0 %= no pain reduction; 100 % = complete pain reduction).

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.

Secondary Outcome Measures

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)

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)

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

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

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)

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)

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)

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)

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.

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)

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)

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.

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.

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

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).

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)

Insomnia Severity Index (sub-study 2)

Consists of self-rated questions which maps sleep difficulties specific to insomnia on a 5 point Likert scale

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)

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

Side-effects (sub-study 2)

Side effects using a specific side effects questionnaire specifically designed for assessment of safety in rTMS studies

Blinding (sub-study 2)

blinding questionnaire

Full Information

NCT ID

NCT04819503

First Posted

March 16, 2021

Last Updated

March 25, 2021

Sponsor

Oslo University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT04819503

Brief Title

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

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Unknown status

Study Start Date

April 1, 2021 (Anticipated)

Primary Completion Date

December 1, 2022 (Anticipated)

Study Completion Date

December 1, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Oslo University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neuropathic Pain, Phantom Limb Pain, Amputation

Keywords

repetitive transcranial magnetic stimulation, spinal anaesthesia

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

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

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Blinding is achieved by inserting a card into the rTMS stimulator which determines whether the patients receive active or sham stimulation. Thus, both experimenter and patients are blinded towards group allocation. Care providers are also blinded to the treatment allocation. The main efficacy analyses will be performed blinded without identification of participants and group allocation.

Allocation

Randomized

Enrollment

20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Active and then sham repetitive transcranial magnetic stimulation

Arm Type

Other

Arm Description

Arm Title

Sham and then active repetitive transcranial magnetic stimulation

Arm Type

Other

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Spinal anaesthesia (sub-study 1)

Intervention Description

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.

Intervention Type

Device

Intervention Name(s)

Repetitive transcranial magnetic stimulation (sub-study 2)

Intervention Description

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

Primary Outcome Measure Information:

Title

Percentage spontaneous pain intensity reduction (sub-study 1)

Description

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

Title

Change in usual pain intensity over the past 24 hours from baseline to 1 week after each treatment (sub-study 2

Description

Time Frame

Average of usual pain scores one week before each treatment (baseline week) and 1 week after each treatment

Secondary Outcome Measure Information:

Title

Intensity of brush induced allodynia (sub-study 1)

Description

Time Frame

Measured before, 5 minutes and 30 minutes after spinal anaesthesia

Title

Intensity of pressure induced allodynia (sub-study 1)

Description

Time Frame

Measured before, 5 minutes and 30 minutes after spinal anaesthesia

Title

Pin-prick sensitivity (sub-study 1)

Description

Time Frame

Measured before, 5 minutes and 30 minutes after spinal anaesthesia

Title

Spontaneous pain intensity right now (sub-study 1)

Description

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

Title

Usual pain intensity over the past 24 hours (sub-study 2)

Description

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.

Title

Pain intensity (sub-study 2)

Description

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

Title

Pain unpleasantness (sub-study 2)

Description

Time Frame

Before, 1 week and 3 weeks after the end of each stimulation period

Title

Pain diary of pain duration, paroxysms and pain interference on sleep (sub-study 2)

Description

Time Frame

Every day 1 week before each stimulation period and up to three weeks after

Title

Proportion of responders (sub-study 2)

Description

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