Surgical Treatments for Postamputation Pain

January 7, 2025 updated by: Max Ortiz Catalan, Prometei Pain Rehabilitation Center
This is a double-blind randomised controlled trial (RCT) which compares the effectiveness of three surgical techniques for alleviating residual limb pain (RLP), neuroma pain and phantom limb pain (PLP). The three surgical treatments are Targeted Muscles Reinnervation (TMR), Regenerative Peripheral Nerve Interface (RPNI), and an active control (neuroma excision and muscle burying). Patients will be follow-up for 4 years.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Residual limb pain (RLP), neuroma pain, and phantom limb pain (PLP) can develop after the loss of a body part and fall within the umbrella term postamputation pain. However, the underlaying causes to postamputation pain are diverse and must be addressed accordingly. Surgical treatments for RLP have become a popular approach and have shown great potential for successful outcomes. The two surgical interventions, Targeted Muscle Reinnervation (TMR) and Regenerative Peripheral Nerve Interface (RPNI), are globally used in pain management therapies.

This is a multi-centre, double-blind, superiority RCT which takes place at 9 hospitals in 7 countries:the Sahlgrenska University Hospital in Gothenburg, Sweden; the Rizzoli Orthopaedic Institute in Bologna, Italy; the University of Alberta Hospital in Edmonton, Canada; Worker Hospital in Santiago, Chile; the NHS Lothian, NHS Clyde & Greater Glasgow, and NHS Grampian, UK; Dandenong Hospital, Monash Health in Melbourne, Australia; the Northwestern Memorial Hospital in Chicago, USA; the University of Michigan Health System in Ann Arbor, Michigan, USA; and within the Massachusetts General Hospital in Boston, USA. One hundred ten participants will be recruited and randomly assigned to one of three surgical treatments (TMR, RPNI, or control) in an equal allocation ratio (n = 37 per group). Each participant will be followed up short term (1, 3, 6, and 12 months post-surgery) and long term (2 and 4 years post-surgery). After the 12-month follow-up, the study will be unblinded for the evaluator and the participants. If the participants are unsatisfied with the outcome of the treatment, they may request one of the other treatments. In such a case, a medical evaluation and further treatment options will be discussed in consultation with the clinical investigator at the site.

The study design is chosen to be able to follow RLP, neuroma pain and PLP intensity before and after surgical treatment as well as to investigate how pain develops up to four years post-surgery. The evaluation methods in the study are based on previously used methods in the literature for RLP-, neuroma- and PLP-related pain research. The questionnaires are previously used in clinical settings.

Study Type

Interventional

Enrollment (Estimated)

110

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Australia
      • Melbourne, Australia
        • Not yet recruiting
        • Dandenong Hospital, Monash Health
        • Contact:
        • Principal Investigator:
          • Michael Lo, MD, PhD
        • Sub-Investigator:
          • Michael Leung, MD, PhD
  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, AB T6G 2B7
        • Not yet recruiting
        • University of Alberta Hospital
        • Contact:
        • Principal Investigator:
          • Adil Ladak, MD, PhD
        • Sub-Investigator:
          • Hollie Power, MD, PhD
        • Sub-Investigator:
          • Jacqueline Hebert, MD, PhD
  • Chile
      • Santiago, Chile
        • Not yet recruiting
        • Worker Hospital
        • Contact:
        • Principal Investigator:
          • Juan Manuel Breyer, MD, PhD
  • Italy
    • Emilia-Romagna
      • Bologna, Emilia-Romagna, Italy, 40136
        • Recruiting
        • Rizzoli Orthopedic Institute
        • Contact:
        • Principal Investigator:
          • Paolo Sassu, MD, PhD
        • Sub-Investigator:
          • Francesca Pedrini, MD
  • Sweden
    • Västra Götaland
      • Mölndal, Västra Götaland, Sweden, 431 80
        • Not yet recruiting
        • Sahlgrenska University Hospital
        • Principal Investigator:
          • Carina Reinholdt, MD, PhD
        • Sub-Investigator:
          • Hannes Granberg, MD
        • Contact:
  • United Kingdom
      • Edinburgh, United Kingdom
        • Not yet recruiting
        • NHS Lothian, NHS Clyde & Greater Glasgow, and NHS Grampian
        • Contact:
        • Principal Investigator:
          • Aidan Roche, MD, PhD
        • Sub-Investigator:
          • Andrew Hart, MD, PhD
        • Sub-Investigator:
          • Lorraine Harrington, MD, PhD
  • United States
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Not yet recruiting
        • Northwestern Memorial Hospital
        • Contact:
        • Principal Investigator:
          • Jason Ko, MD, PhD
        • Sub-Investigator:
          • Gregory Dumanian, MD, PhD
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Not yet recruiting
        • Massachusetts General Hospital
        • Contact:
        • Principal Investigator:
          • Ian Valerio, MD, PhD
        • Sub-Investigator:
          • Kyle Eberlin, MD, PhD
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • Not yet recruiting
        • University of Michigan Health System
        • Contact:
        • Principal Investigator:
          • Paul Cederna, MD, PhD
        • Sub-Investigator:
          • Theodore Alexander Kung, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • The participant must have a major limb amputation.
  • The participant is ≥ 18 years old at the time of consent.
  • The participant must be in generally good health to undergo a surgical intervention, as per the clinical investigator's opinion.
  • Time since the last amputation must be over a year at the time of consent.
  • The participant must have an average residual limb pain score equal or greater than 4 on the Numerical Rating Scale (NRS, 0-10) after the baseline period.
  • If the participant has been prescribed pharmacological treatments for pain, there must be no variations in dosage (steady consumption) for at least 1 month before the screening visit.
  • If the participant has been prescribed non-pharmacological treatments for pain, such as spinal cord stimulation, transcutaneous electrical nerve stimulation, and mirror therapy, the treatment must have ended at least 1 month before the screening visit.
  • The participant must have a stable prosthetic fitting for at least a month before the screening visit.
  • The participant has a sufficient understanding of the language in which the assessments will be conducted, as per the clinical investigator's opinion.

Exclusion Criteria:

  • Neurological or other conditions that affect nerve regeneration for the nerve to be treated.
  • Active infection in the residual limb.
  • Prior RPNI or TMR surgery of the nerve to be treated (with painful neuroma) to address postamputation pain.
  • Mental disorders (e.g., schizophrenia, paranoia, psychosis, etc.), reluctance, or language difficulties that result in difficulty understanding the meaning of study participation.
  • Ongoing participation in a clinical study that the clinical investigator deems detrimental to participation in this study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Targeted Muscle Reinnervation (TMR)
The surgical procedure comprises three steps: preparation of the donor nerve, identification of a motor branch to the targeted muscle, and nerve coaptation. To prepare the donor nerve, the surgeon will identify the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Next, the surgeon will identify a motor branch to a nearby target muscle and will confirm muscle contraction using a hand-held nerve stimulator. The motor branch to the target muscle will be transected as close as possible to its entry point without tension. In the final step, the previous nerve stump from which the neuroma was resected will be transferred and coapted to the newly severed motor branch that innervates the target muscle and secured by 2-3 non-resorbable monofilament sutures. The surgery time is approximately 2-3 hours and it takes place in the hospital.
Procedure: Targeted Muscle Reinnervation (TMR)
Surgical procedure used to rewire injured proximal nerves to motor nerves directly innervating an otherwise redundant target muscle.
Active Comparator: Regenerative Peripheral Nerve Interface (RPNI)
The RPNI procedure involves construction of a residual peripheral nerve split into several nerve fascicles and implanted into free skeletal muscle grafts. First, the surgeon identifies the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Then, a longitudinal intraneural dissection will be performed exposing its fascicles. Next, autologous muscle grafts will be harvested from a healthy donor site, and the dissected nerve stumps will be placed parallel to the muscle fibers. The nerve stump will be secured to the muscle graft, thereafter the graft will be wrapped around the nerve stump and anchored in the folded graft, thus creating an RPNI. This will be repeated for each fascicle obtained from splitting the transected nerve. Lastly, the RPNIs will be placed in a protected area. The surgery time is approximately 2-3 hours and it takes place in the hospital.
Procedure: Regenerative Peripheral Nerve Interface (RPNI)
Surgical procedure where the the nerve is split into fascicles and wrapped in free muscle grafts.
Active Comparator: Standard neuroma treatment, neuroma excision, and muscle burying
The standard neuroma treatment, also called neuroma transposition, includes excision of the terminal neuroma and burying the nerve into an adjacent deep muscle.The standard neuroma treatment entails the excision of the terminal neuroma and then implanting the nerve into an adjacent muscle. Firstly, the surgeon will identify the nerve with a painful neuroma and thereafter resect the neuroma up to healthy fascicles. Next, the surgeon will identify a nearby muscle which is not involved in joint motion and has limited output opportunities for the nerve. The nerve will then be channeled at least 1 cm inside the muscle without applying any tension to it and secured by 1-2 non-resorbable monofilament sutures. The identified nerve with the painful neuroma will not be treated with any additional therapy than the resection (e.g., diathermy, pharmacotherapy, crushing, etc.). The surgery time is approximately 1-2 hours and it takes place in the hospital.
Procedure: Standard neuroma treatment, neuroma excision, and muscle burying
Surgical procedure where the neuroma is excised and the nerve stump is buried in an adjacent deep muscle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Residual limb pain intensity
Time Frame: Baseline to 12-month post-surgery
Difference in residual limb pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-month follow-up visit.
Baseline to 12-month post-surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neuroma pain intensity
Time Frame: Baseline to 12-month post-surgery
Difference in neuroma pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-month follow-up visit.
Baseline to 12-month post-surgery
Phantom limb pain intensity
Time Frame: Baseline to12-month post-surgery
Difference in phantom limb pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-months follow-up visit.
Baseline to12-month post-surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Prometei Pain Rehabilitation Center

Collaborators

Massachusetts General Hospital
Göteborg University
University of Michigan
University of Alberta
Istituto Ortopedico Rizzoli
Vastra Gotaland Region
NHS Lothian
Northwestern Memorial Hospital
NHS Grampian
NHS Greater Clyde and Glasgow
Dandenong Hospital
Hospital del Trabajador de Santiago

Investigators

  • Principal Investigator: Max Ortiz Catalan, PhD, Prometei Pain Rehabilitation Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 20, 2023

Primary Completion (Estimated)

June 1, 2026

Study Completion (Estimated)

June 1, 2029

Study Registration Dates

First Submitted

July 12, 2021

First Submitted That Met QC Criteria

August 11, 2021

First Posted (Actual)

August 17, 2021

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

January 7, 2025

Last Verified

January 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2021-02346

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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