Mechanisms and Treatment of Post-amputation Neuropathic Pain

NCT04819503 | Terminated

• 1 other identifier: 77110
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

Neuropathic Pain; Phantom Limb Pain; Amputation

Keywords

repetitive transcranial magnetic stimulation; spinal anaesthesia

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (21)

• Intensity of brush induced allodynia (sub-study 1)

  Measured before, 5 minutes and 30 minutes after spinal anaesthesia

• Intensity of pressure induced allodynia (sub-study 1)

  Measured before, 5 minutes and 30 minutes after spinal anaesthesia

• Pin-prick sensitivity (sub-study 1)

  Measured before, 5 minutes and 30 minutes after spinal anaesthesia

• Spontaneous pain intensity right now (sub-study 1)

  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)

  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.

Study Arms (2)

Active and then sham repetitive transcranial magnetic stimulation

OTHER

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); Device: Repetitive transcranial magnetic stimulation (sub-study 2)

Sham and then active repetitive transcranial magnetic stimulation

OTHER

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); Device: Repetitive transcranial magnetic stimulation (sub-study 2)

Interventions

Spinal anaesthesia (sub-study 1) DRUG

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.

Active and then sham repetitive transcranial magnetic stimulation; Sham and then active repetitive transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (sub-study 2) DEVICE

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

Active and then sham repetitive transcranial magnetic stimulation; Sham and then active repetitive transcranial magnetic stimulation

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)
• Other pain conditions more severe than phantom and residual limb pain.
• Inability to understand the protocol or to fill out the forms

Sponsors & Collaborators

• Oslo University Hospital: lead

Study Sites (1)

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

Oslo, 0424, Norway

Location

MeSH Terms

Conditions

Neuralgia; Phantom Limb

Interventions

Anesthesia, Spinal; Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Perceptual Disorders; Neurobehavioral Manifestations; Pain, Postoperative; Postoperative Complications; Pathologic Processes

Intervention Hierarchy (Ancestors)

Anesthesia, Conduction; Anesthesia; Anesthesia and Analgesia; Magnetic Field Therapy; Therapeutics

Study Officials

• Audun Stubhaug, DMedSci

  Oslo University Hospital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD

Model Details: 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

Study Record Dates

• First Submitted: March 16, 2021
• First Posted: March 29, 2021
• Study Start: January 1, 2021
• Primary Completion: December 3, 2021
• Study Completion: December 3, 2021
• Last Updated: November 29, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, 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.

Locations

NO (1)