Mechanisms and Treatment of Post-amputation Neuropathic Pain

• ClinicalTrials.gov Identifier: NCT04819503
• Recruitment Status: Not yet recruiting
• First Posted: March 29, 2021
• Last Update Posted: March 29, 2021
• Sponsor: Oslo University Hospital
• Information provided by (Responsible Party): Nadine Farnes, Oslo University Hospital

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.

Condition or disease	Intervention/treatment	Phase
Neuropathic Pain; Phantom Limb Pain; Amputation	Drug: Spinal anaesthesia (sub-study 1); Device: Repetitive transcranial magnetic stimulation (sub-study 2)	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• 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
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes 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.

• Primary Purpose: Treatment
• 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
• Estimated Study Start Date: April 1, 2021
• Estimated Primary Completion Date: December 1, 2022
• Estimated Study Completion Date: December 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Active and then sham repetitive transcranial magnetic stimulation; 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); 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.; Device: Repetitive transcranial magnetic stimulation (sub-study 2); 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
Sham and then active repetitive transcranial magnetic stimulation; 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); 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.; Device: Repetitive transcranial magnetic stimulation (sub-study 2); 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

Outcome Measures

Primary Outcome Measures :

1. Percentage spontaneous pain intensity reduction (sub-study 1) [ Time Frame: Maximum reduction during a time interval from 5-60 minutes after spinal anaesthesia ]
   Measured on an 11-point numerical rating scale (0 %= no pain reduction; 100 % = complete pain reduction).
2. Change in usual pain intensity over the past 24 hours from baseline to 1 week after each treatment (sub-study 2 [ Time Frame: Average of usual pain scores one week before each treatment (baseline week) and 1 week after each treatment ]
   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 :

1. Intensity of brush induced allodynia (sub-study 1) [ Time Frame: Measured before, 5 minutes and 30 minutes after spinal anaesthesia ]
   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)
2. Intensity of pressure induced allodynia (sub-study 1) [ Time Frame: Measured before, 5 minutes and 30 minutes after spinal anaesthesia ]
   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)
3. Pin-prick sensitivity (sub-study 1) [ Time Frame: Measured before, 5 minutes and 30 minutes after spinal anaesthesia ]
   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
4. Spontaneous pain intensity right now (sub-study 1) [ Time Frame: Measured before, and 5, 10, 15, 20, 25, 30, 60, 90 and 120 minutes after spinal anaesthesia ]
   Measured on a 0-10 numerical rating scale where 0 indicates no pain and 10 indicates worst pain imaginable
5. Usual pain intensity over the past 24 hours (sub-study 2) [ 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. ]
   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)
6. Pain intensity (sub-study 2) [ Time Frame: Before, 1 week and 3 weeks after the end of each stimulation period ]
   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)
7. Pain unpleasantness (sub-study 2) [ Time Frame: Before, 1 week and 3 weeks after the end of each stimulation period ]
   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)
8. Pain diary of pain duration, paroxysms and pain interference on sleep (sub-study 2) [ Time Frame: Every day 1 week before each stimulation period and up to three weeks after ]
   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)
9. Proportion of responders (sub-study 2) [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
   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.
10. Percentage pain intensity reduction (sub-study 2) [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
    Percentage pain intensity reduction on an 11-point numerical rating scale (0 %= no pain reduction; 100% complete pain reduction)
11. Pain interference (sub-study 2) [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
    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)
12. Neuropathic Pain Symptom Inventory (sub-study 2) [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
    Measures mean intensity of 10 neuropathic symptoms during the last 24 hours on 11-point (0-10) numerical scales.
13. Short form McGill Pain questionnaire (sub-study 2) [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
    The sensory and affective score of the short form McGill Pain questionnaire which consists of 15 items measured on a 4 point scale.
14. Hospital Anxiety and Depression Scale (sub-study 2) [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
    The Hospital Anxiety and Depression Scale includes 14 items scored as anxiety and depression scores, 7 items assessing depression and 7 anxiety
15. Pain Catastrophizing Scale (sub-study 2) [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
    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).
16. Patient Global Impression of Change (sub-study 2) [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
    Consists of 7 items to evaluate the subjective improvement or deterioration (from very much improved to very much deteriorated)
17. Insomnia Severity Index (sub-study 2) [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
    Consists of self-rated questions which maps sleep difficulties specific to insomnia on a 5 point Likert scale
18. Patient-Specific Functional Scale (sub-study 2) [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
    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)
19. Executive functioning using the CANTAB battery [ Time Frame: Before,1 week and 3 weeks after the end of each stimulation period ]
    Composite score and individual scores of the paired associates learning test, stop signal task, spatial working memory test and the multitasking test
20. Side-effects (sub-study 2) [ 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 ]
    Side effects using a specific side effects questionnaire specifically designed for assessment of safety in rTMS studies
21. Blinding (sub-study 2) [ Time Frame: 3 weeks after the end of each stimulation period ]
    blinding questionnaire

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Nadine Farnes, MSc; 004723026161; nafarn@ous-hf.no

Contact: Per Hansson, PhD; phanss2@ous-hf.no

Locations

Norway

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

Oslo, Norway, 0424

Contact: Audun Stubhaug, PhD audun.stubhaug@ous-hf.no),

Contact: Per Hansson, PhD phanss2@ous-hf.no

Sponsors and Collaborators

Oslo University Hospital

Investigators

• Study Director: Audun Stubhaug, DMedSci; Oslo University Hospital

More Information

• Responsible Party: Nadine Farnes, M.S., Oslo University Hospital
• ClinicalTrials.gov Identifier: NCT04819503
• Other Study ID Numbers: 77110
• First Posted: March 29, 2021
• Last Update Posted: March 29, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Deidentified individual participant data collected during the trial will be available to other researchers who provide a methodologically sound proposal, and who adhere to institutional guidelines.
• Supporting Materials: Study Protocol; Informed Consent Form (ICF)
• Time Frame: All the individual participant data collected during the trial will be available after deidentification, beginning 3 months and lasting 5 years after publication.
• Access Criteria: Requestors will need to sign a data access agreement.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nadine Farnes, Oslo University Hospital:

repetitive transcranial magnetic stimulation; spinal anaesthesia

Additional relevant MeSH terms:

Neuralgia; Phantom Limb; Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Perceptual Disorders; Neurobehavioral Manifestations; Pain, Postoperative; Postoperative Complications; Pathologic Processes; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs