Nervous System Diseases

Symptoms and General Pathology

All Conditions

Behaviors and Mental Disorders

Neoplasms

Rare Diseases

Neuralgia

Pain

Phantom Limb

Neuroma

Peripheral Nervous System Diseases

Neuromuscular Diseases

Neurologic Manifestations

Perceptual Disorders

Neurobehavioral Manifestations

Pain, Postoperative

Postoperative Complications

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Chronic Graft Versus Host Disease

Ten amputees will recieve magnetic resonance-guided focused ultrasound (MRgFUS) treatment aimed to ablate neromas, which are beleived to cuase phantom / residual limb pain

Ten amputees wil recieve a magnetic resonance-guided focused ultrasound treatment aimed at ablating neuromas, which are believe to contribute to their phantom / residual limb pain

Magnetic resonance-guided focused ultrasound

Elon Eisenberg, Prof

Elon Eisenberg

AIM: To provide initial information on the efficacy (pain reduction) and safety of focused ultrasound surgery for the ablation of stump neuromas in amputees with chronic neuropathic pain.

PARTICIPANTS: The study will include 10 amputees (men/women age \>18 years old) with chronic (\>3 months) phantom/residual limb pain (NPS ≥ 4).

DESIGN: Patients potentially qualifying for the study will be offered an Informed Consent to sign prior to further evaluation. Those who accept will sign the informed consent, complete study questionnaires and be evaluated in terms of inclusion/exclusion criteria. Specifically, a complete medical history will be obtained to determine the patient's general health status, current symptoms, frequency and dosage of their current analgesic intake etc. Baseline pain scores will be established. If not performed within six months prior to the evaluation, a contrast MRI of the stump will be performed. Patients not meeting the study criteria will be exited from the study as screen failures and not be included in analyses. All qualifying patients will complete a baseline MRI exam on treatment day. Any patient not meeting study criteria at Imaging will be exited as screen failures.

After completion of the MRI exam, qualifying patients will proceed to the ExAblate treatment. These patients will then be followed for 6-months post-ExAblate treatment; the patients will complete study follow-up questionnaires at 1, 3 days, 1 and 2 weeks, and 1, 3 and 6 months after treatments. Follow-up visits will take place 1 week and 1, 3 and 6 months after treatment to assess their pain status, their quality of life and safety. Data regarding dosage and frequency of analgesic intake for the management of post amputation NP will be collected. Relevant cost data will be collected in order to enable an assessment of the total cost of the procedure.

I. BACKGROUND:

In 2005, 1.6 million people were estimated to be living with limb loss (3). Up to 70% of the patients who undergo limb amputation develop chronic phantom/residual limb pain. A state-of-art understanding of the pathophysiologic basis underlying post-amputation pain suggests that neuroma formation by regenerative sprouting, leading to increased ectopic afferent input is the predominant mechanism involved in NP. Post-amputation pain is often persistent, resistant to treatment and leads to considerable disability. Therefore, new "anti-nueromas" treatments are required.

Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive procedure that combines two technologies:

* Focused ultrasound (FUS) waves which are converted to thermal energy at precise focal point, causes tissue temperature increase, resulting in irreversible thermal ablation of the tissue.
* MRI: Three-dimensional imaging of the tissue and the ultrasound beam in real time enhances the safety and effectiveness of the procedure by allowing:

  * Anatomical planning of the treatment.
  * Real time thermal imaging enables of the and its surrounding tissues. The safety and effectiveness of MRgFUS has been shown in a prospective, randomized (3:1), two-arm, sham-controlled, multicenter, international clinical study with a sham-crossover option in patients with metastatic bone pain, who were not suitable candidates for radiation therapy. A much higher proportion of MRgFUS patients than controls were responders (65.2% vs 18.9%).

II. AIMS:

To provide initial information on the efficacy (pain reduction) and safety of focused ultrasound surgery for the ablation of stump neuromas in amputees with chronic neuropathic pain.

III. PARTICIPANTS:

The study will include 10 amputees with chronic phantom/residual limb pain.

Inclusion Criteria

1. Men and women amputees, aged 18 and older
2. Patients who are able and willing to give consent and able to attend all study visits
3. Patients who are suffering from post-amputation phantom/residual limb pain for at least 3 months
4. Patient with average pain intensity on a 0-10 numerical pain scale (NPS) ≥ 4 during a 3 days period prior to enrollment irrespective of medication use
5. Patient whose targeted (treated) lesion is deeper than 10-mm from the skin
6. Targeted (treated) neuroma is clearly visible by non-contrast MRI, and ExAblate MRgFUS device accessible Exclusion Criteria

1. Patients with any acute or unstable medical condition that is expected to hinder them from completing this study 2. Patients with standard contraindications for MR imaging. 3. Known intolerance or allergies to the MRI contrast agent (e.g. Gadolinium or Magnevist) including advanced kidney disease 4. Individuals who are not able or willing to tolerate the required prolonged stationary position during treatment 5. Are participating or have participated in another clinical trial in the last 30 days 6. Patients with persistent undistinguishable pain (pain source unidentifiable) 7. Patients whose neuroma is \< 10-mm from the skin, blood vessels or bone 8. Patients with more than three neuromas in the affected limb 9. Targeted (treated) neuroma is NOT visible by non-contrast MRI 10. Targeted neuroma is not accessible to ExAblate due to scar tissue or any other reason

IV. STUDY DESIGN Patients potentially qualifying for the study will be offered an Informed Consent to sign prior to further evaluation. Those who accept will sign the informed consent, complete study questionnaires and be evaluated in terms of inclusion/exclusion criteria. Specifically, a complete medical history will be obtained to determine the patient's general health status, current symptoms, frequency and dosage of their current analgesic intake etc. Baseline pain scores will be established. If not performed within six months prior to the evaluation, a contrast MRI of the stump will be performed. Patients not meeting the study criteria will be exited from the study as screen failures and not be included in analyses. All qualifying patients will complete a baseline MRI exam on treatment day. Any patient not meeting study criteria at Imaging will be exited as screen failures.

Qualifying patients will proceed to the ExAblate treatment. These patients will then be followed for 6-months post-ExAblate treatment; patients will complete study follow-up questionnaires at 1, 3 days, 1 and 2 weeks, and 1, 3 and 6 months after treatments. Follow-up visits will take place 1 week and 1, 3 and 6 months after treatment to assess their pain status, their quality of life and safety. Data regarding dosage and frequency of analgesic intake for the management of post amputation NP will be collected.

Outcome measures Primary endpoint: Change from baseline in the average daily pain intensity, measured for 3 consecutive days, on the Numerical Pain Scale (NPS), an 11-point numeric rating scale.

Secondary endpoints:

* Change from baseline in the maximum daily pain intensity, measured for 3 consecutive days, on the NPS.
* Change from the baseline in the minimum daily pain intensity, measured for 3 consecutive days, on the NPS.
* Change from the baseline in the consumption of analgesic medications used for the post amputation NP (i.e., increase, unchanged, decreased).
* Change from baseline in Short-Form McGill Pain Questionnaire (SF-MPQ) score
* Change from the baseline in the Pittsburgh sleep quality index (PSQI).
* Change from the baseline in the European Quality of Life Five-Dimensional (EQ-5D) questionnaire.
* Change from the baseline in the Brief Pain Inventory (BPI).
* Clinician's Global Impression of Change from the baseline.
* Patient's Global Impression of Change from the baseline.
* Change from the baseline in MRI findings in the treated neuroma(s).

Treatment Procedure

* Baseline MRI examinations (without contrast) will be performed to identify the neuroma size, location and extent and device accessibility as well as to evaluate the patient's ability to cooperate during the ExAblate procedure. If at this point it is determined that the patient does not meet all Inclusion and Exclusion criteria and cannot be treated, the patient will be exited from the study. These patients will be considered screening failures, and will not be included in any of the safety or efficacy endpoint analyses.
* If the patient meets all study criteria, the patient will have the ExAblate treatment during this same MRI examination session.
* An IV line will be positioned for the delivery of medications and will be maintained throughout the procedure. Monitoring of heart rate and pO2 will be maintained throughout the procedure using standard MR-compatible monitoring devices. The patients' skin will be closely examined for hair in the treatment path. If necessary, the hair will be removed around the treatment area and the skin will be cleaned, for example with alcohol, from any oil based skin product. Degassed water and possibly an acoustic gel pad will be placed atop of the transducers' window to generate acoustic coupling.
* Patients will be positioned on the ExAblate therapy bed in a selected position according to the planned treatment area. The patient's area of treatment may be placed in a special-purpose imaging coil and positioned in the magnet in the treatment position.
* An MRI scan will be performed with T2 and T1 weighted sequences in all three orientations to localize and measure the target neuroma(s) to be treated.
* Any prior scar will be identified on the image and the ultrasound treatment plan will be planned to avoid sonicating through the scar whenever possible.
* If the neuroma(s) to be treated is identifiable on the MR images, accessible by the device for treatment, and the patient meets all inclusion and exclusion criteria, treatment planning will begin.
* The physician will trace the neuroma(s) in the targeted area.
* The physician will draw the treatment volume using MR images from one or more scan orientations using the following guidelines:
* Up to three well defined neuromas can be treated.
* A central point on the neuroma (depending on patient anatomy) will be sonicated with a low thermal dose, to verify targeting accuracy in the patient. Target placement and transducer positioning will be adjusted as necessary.
* If at this point it is determined that the patient cannot be treated, he or she will be withdrawn from the magnet and the IV line and pulse oximeter will be removed. The patient will be taken to the recovery area for observation and release. Follow-up will consist of a phone call at 1-week post treatment. These patients will be considered screen failures and will not be included in the efficacy analysis.
* Prior to the delivery of any treatment sonications the patient will receive analgesia and sedation or other measures to reduce pain and limit patient motion, and help alleviate anxiety and claustrophobia. Monitoring of heart rate and pO2 saturation will be maintained throughout the procedure.
* Treatment will begin. Sonications will be performed on successive points \[sonication duration between 15 - 60 sec\]. The effect of each sonication will be measured by MR using phase map imaging, reflecting the temperature-dependent change in the proton resonance frequency. Acoustic power will be adjusted throughout the treatment, to achieve temperature between 65 and 85 degrees from MR thermal images at the targeted neuroma.
* Sonications will continue until the prescribed targeted area has been treated. The goal is that the total time from 1st to last sonication will be limited to 180-minutes, or to patient tolerance.
* If no more than 3 planned sonications can be performed using therapeutic energies, then these patients will be considered as screen failures, and will not be included in the intent-to-treat analysis. However, they will be added to the Safety analyses. Criteria to terminate treatment include patient intolerance to the treatment, targeting difficulties due to patient motion or a decision of the treating physician.
* Immediately post-treatment, a series of MR scans will be performed. The scanning will include T2 weighted sequences and T1 weighted contrast enhanced sequences to evaluate general anatomy and to assess treatment effect.
* The patient will be taken off the therapeutic table and escorted to a recovery area for observation period pending release from hospital.
* All MR exams taken during the study will be archived for later analyses.
* If during the treatment session, the physician did not complete the planned treatment, and determines that it would be to the benefit of the patient to continue treatment at a second session, a second treatment session may be completed within two (2) weeks of the first treatment. However, up to three painful neuromas can be treated under this protocol and the purpose of the second treatment is to complete the original treatment plan. This protocol does not allow for a second treatment due to continued pain at the treated site or the treatment of additional painful lesions. The preparation procedures for the second treatment will be the same as the first. No more than two treatments should be performed within a two (2) week period.

Follow-up Telephone follow-up visits will be completed at 1 and 3 days, and 2 weeks post treatment. Clinic visits will be completed at 1 week and 1, 3 and 6 months post-ExAblate treatment. Patients will be evaluated for general health, efficacy measurements as well as for device/procedure related AEs that may have occurred during the follow-up period. Additional data regarding dosage and frequency of analgesic intake for the management of NP will also be collected. For phone visits, study personnel will contact the patient, inquire about AEs and question the patient according to the pain questionnaire, pain medication intake. The study personnel will then sign and date the completed forms. A follow-up MRI to assess the effects on the treated neuroma(s) will be performed four months after treatment.

Focused Ultrasound Treatment of Stump Neuromas for the Relief of Chronic Post-Amputation Neuropathic Pain

Change from baseline in the average daily pain intensity, measured for 3 consecutive days, on the Numerical Pain Scale (NPS), an 11-point numeric rating scale.

Rambam Health Care Campus

Head, Pain Research Unit

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.

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.

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.

Surgical procedure used to rewire injured proximal nerves to motor nerves directly innervating an otherwise redundant target muscle.

Targeted Muscle Reinnervation (TMR)

Surgical procedure where the the nerve is split into fascicles and wrapped in free muscle grafts.

Regenerative Peripheral Nerve Interface (RPNI)

Surgical procedure where the neuroma is excised and the nerve stump is buried in an adjacent deep muscle.

Standard neuroma treatment, neuroma excision, and muscle burying

Emily Pettersen, MSc

Max Ortiz Catalan, PhD

Jason Ko, MD, PhD

Gregory Dumanian, MD, PhD

Ian Valerio, MD, PhD

Kyle Eberlin, MD, PhD

Paul Cederna, MD, PhD

Theodore Alexander Kung, MD, PhD

Michael Lo, MD, PhD

Michael Leung, MD, PhD

Adil Ladak, MD, PhD

Hollie Power, MD, PhD

Jacqueline Hebert, MD, PhD

Juan Manuel Breyer, MD, PhD

Paolo Sassu, MD, PhD

Francesca Pedrini, MD

Carina Reinholdt, MD, PhD

Hannes Granberg, MD

Aidan Roche, MD, PhD

Andrew Hart, MD, PhD

Lorraine Harrington, MD, PhD

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.

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.

Surgical Treatments for Postamputation Pain

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.

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.

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.

Vastra Gotaland Region

Göteborg University

Chalmers University of Technology

Istituto Ortopedico Rizzoli

Hospital del Trabajador de Santiago

NHS Lothian

NHS Greater Clyde and Glasgow

NHS Grampian

Northwestern Memorial Hospital

University of Michigan

Massachusetts General Hospital

Dandenong Hospital

The Bionics Institute of Australia

University of Alberta

Center for Bionics and Pain Research

Professor

Chronic Pain

Acute Pain

Acute Graft Versus Host Disease

Standard medical therapy and 30 to 60 days of peripheral nerve stimulation starting within 7 days after surgery

Up to 60 days of peripheral nerve stimulation

Peripheral nerve stimulation

Medications, physical therapy, or other pain treatments

Standard Medical Therapy

Denise Lester, MD

Limb loss is frequently associated with postamputation pain that can be challenging to treat and often involves opioids. Advances in the field of neuromodulation has led to development of an intentionally reversible percutaneous peripheral nerve stimulation (PNS) system that has had promising results when treating chronic postamputation pain. PNS may offer sustained pain relief even after the treatment period has ended. Currently, there is no convincing evidence regarding the role of PNS in the acute postoperative period, which may be a critical time to control pain as those with higher pain appear to be at higher risk for developing persistent post-procedural pain. The investigators of this study aim to evaluate the feasibility and effects of PNS in the acute postoperative period and determine the feasibility of completing a randomized controlled treatment outcome study.

16 patients with new nontraumatic transfemoral or transtibial amputation will be enrolled in the study

Having met inclusion criteria, the patients will be randomized to experimental or control groups

Patients in the experimental group undergo placement of PNS leads within 7 days of amputation surgery

Patients in both groups will be treated with standard pharmacologic and nonpharmacologic pain therapies and evaluated weekly for 8 weeks, then at 3, 6, and 12 months postamputation

Postoperative Peripheral Nerve Stimulation for Management of Post-amputation Pain

Effects of Postoperative Percutaneous Peripheral Nerve Stimulation on Acute and Chronic Amputation Pain

Using the Brief Pain Inventory-Short Form (BPI-SF) questionnaire, subjects were asked to rate their PLP over the past 24 hours on a scale of "0"=no pain to "10"=worst pain they have ever experienced. A lower score is better. Data from Weeks 1-4 and Weeks 5-8 were averaged to obtain a numerical score for these time points.

Using the Brief Pain Inventory-Short Form (BPI-SF) questionnaire, subjects were asked to rate their RLP over the past 24 hours on a scale of "0"=no pain to "10"=worst pain they have ever experienced. A lower score is better. Data from Weeks 1-4 and Weeks 5-8 were averaged to obtain a numerical score for these time points.

The number of subjects prescribed any opioid medication and any dose. Data from Weeks 1-4 and Weeks 5-8 were averaged to obtain a numerical score for these time points.

Opioid consumption (daily OME) over time was collected for all subjects.

FIM mobility subscores were recorded by a physical therapist to measure the ability to walk, use a wheelchair, transfer to tub/shower, transfer to toilet, and mobility in bed, chair, and wheelchair. Scores range from "1" = subject requires total assistance for the task to "7" = complete independence. A higher score is better.

Using the Brief Pain Inventory-Short Form (BPI-SF) questionnaire, subjects were asked to rate how much pain has interfered with daily activities over the past 24 hours on a scale of "0" = no interference to "10" = completely interferes with activities. A lower score is better.

Self-report measure PGIC reflects a patient's belief about the efficacy of treatment. PGIC is a 7 point scale depicting a patient's rating of overall improvement. Patients rate their change as

1 = "very much improved," 2 = "much improved," 3 = "minimally improved," 4 = "no change," 5 = "minimally worse," 6 = "much worse," or 7 = "very much worse." A lower score is better.

Pain catastrophizing is the tendency to magnify the threat value of a pain stimulus and to feel helpless in the presence of pain. This is further characterized by the inability to prevent or inhibit pain-related thoughts surrounding a painful event. Pain catastrophizing affects how individuals experience pain. The PCS is a 13-item inventory of statements in which the subject is asked to rate the degree to which they agree, on a scale of "0" = not at all to "4" = all the time. The responses for each item are added for a total PCS score (range 0-52). A lower score is better.

The PDI is designed to measure the degree to which aspects of life are disrupted by chronic pain. The impact of pain on various aspects of life (e.g. family/home responsibilities, recreation, social activity, occupation, sexual behavior, self-care, and life-support activities) are recorded on a 10-point scale from "0" = no disability to "10" = worst disability. The sum of scores is recorded for a total PDI score (range 0-70). A lower score is better.

Percent of Group that was readmitted to the hospital within 30 days following hospital discharge.

Hospital LOS was calculated from day of surgery to day of discharge from inpatient hospital ward to rehabilitation facility.

Hunter Holmes Mcguire Veteran Affairs Medical Center

Subjects in the Control Group were not at risk for PNS Lead Reimplantation because they did not undergo implantation of any peripheral nerve stimulator leads. Other \[Not Including Serious\] Adverse Events were not monitored/assessed in the Control Arm/Group.

Up to 60 days of PNS starting within 7 days after major lower limb amputation surgery. Subjects also received standard medical therapy (SMT). SMT is defined as pharmacotherapy, physical therapy, or other therapies.

Peripheral Nerve Stimulation (PNS)

Subjects received SMT only after major lower limb amputation surgery. SMT is defined as pharmacotherapy, physical therapy, or other therapies.

Control

Total

Age, Categorical

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

United States

Region of Enrollment

Perineural Catheter Infusion

Taking Opioids Preoperatively

Level of Amputation

Indication for Surgery

Several participants underwent unanticipated amputation revisions, which has the potential to contribute to worsening pain and the need for increased opioids, which may significantly confound results. Subjects were instructed to use the device continuously, and the effects of PNS therapy may be impacted by the number of hours the device was utilized by the patient. Variations in subject compliance with device usage may impact outcomes.

Dr. Denise Lester

Baseline

Weeks 1-4

Weeks 5-8

Month 3

Subjects who completed up to 60 days of peripheral nerve stimulation (PNS) and standard medical therapy (SMT) or (SMT) only.

Average Phantom Limb Pain (PLP) Score

Average Residual Limb Pain (RLP) Score

Worst Phantom Limb Pain (PLP) Score

Worst Residual Limb Pain (RLP) Score

Best Phantom Limb Pain (PLP) Score

Best Residual Limb Pain (RLP) Score

Hospital Discharge

Week 12

Between Weeks 1-4 and Weeks 5-8, three subjects in the PNS Group terminated due to unrelated medical events (2) or withdrew consent (1). After Week 12, two subjects in the Control Group terminated due to unrelated medical events or withdrew consent (data for one subject was collected prior to withdrawal).

Number Taking Opioids

Preop

Average Oral Morphine Equivalents (OME)

Walk (Preop)

Walk (Week 4)

Walk (Week 8)

Wheelchair (Preop)

Wheelchair (Week 4)

Wheelchair (Week 8)

Tub/Shower Transfer (Preop)

Tub/Shower Transfer (Week 4)

Tub/Shower Transfer (Week 8)

Toilet Transfer (Preop)

Toilet Transfer (Week 4)

Toilet Transfer (Week 8)

Bed/Chair/Wheelchair Mobility (Preop)

Bed/Chair/Wheelchair Mobility (Week 4)

Bed/Chair/Wheelchair Mobility (Week 8)

Functional Independence Measure (FIM) Scores

Week 4

Week 8

Subjects who were enrolled in the study and for whom this data was collected.

Pain Interference

Patient Global Impression of Change (PGIC)

Pain Catastrophizing Scale (PCS)

Pain Disability Index (PDI)

30-day Readmission Rate

Hospital Length of Stay (LOS)

Standard medical therapy and 30 to 60 days of peripheral nerve stimulation starting within 7 days after surgery

Peripheral nerve stimulation: Up to 60 days of peripheral nerve stimulation

Standard Medical Therapy: Medications, physical therapy, or other pain treatments

Standard medical therapy only

Standard Medical Therapy: Medications, physical therapy, or other pain treatments

Standard Medical Therapy (SMT)

Overall Study

In this operation, the surgeon will make a skin incision and carefully identify nerves that were likely to have been injured during the amputation surgery. These nerves are then "cleaned up" to be rerouted and connected to smaller nerves that control individual muscles. The connection to nerves that run into muscles is thought to be helpful in directing the nerve healing process and reducing the risk of developing pain in the future. This operation takes 2 - 4 hours and occurs in the hospital. Follow up requires six to seven clinic visits with the surgeon over the course of one year, at which time standard questionnaires will be used to assess pain.

In this operation, the surgeon will make a skin incision and carefully identify nerves that were likely to have been injured during the amputation surgery. The nerves are then "cleaned up" to enhance the possibility of healthy healing. Then the surgeon takes a small sample from a muscle (usually one close by to the nerves that are being operated on but sometimes through a second incision in the arm or leg, depending on the exact medical situation) and form something called a "muscle graft". The muscle graft is used to wrap the cleaned ends of the nerves mentioned above. This is thought to be helpful in directing the nerve healing process and reducing the risk of developing pain in the future. This operation takes 1 - 3 hours and occurs in the hospital. Follow up requires six to seven clinic visits with the surgeon over the course of one year, at which time standard questionnaires will be used to assess pain.

In this operation, the surgeon will make a skin incision and carefully identify nerves that were likely to have been injured during the amputation surgery. The nerves are then "cleaned up" to enhance the possibility of healthy healing. The surgeon will then identify a local muscle along with a small artery and vein that supply blood to part of the muscle. A small sample of muscle, still attached to the artery and vein, is then created. The nearby nerves are then nestled into this segment of muscle that is still connected to the artery and vein. This is thought to be helpful in directing the nerve healing process and reducing the risk of developing pain in the future. This operation takes 2 - 4 hours and occurs in the hospital. Follow up requires six to seven clinic visits with the surgeon over the course of one year, at which time standard questionnaires will be used to assess pain.

Surgical procedure to connect injured proximal nerve stumps to motor nerve branches directly innervating a muscle

Surgical procedure to wrap the ends of injured nerves in small muscle grafts

RPNI

Surgical procedure that creates a small muscle graft that is both denervated and vascularized, which will then receive the damaged nerve ending

VDMT

Sami Tuffaha, MD

Amputees often suffer from relentless pain and disability resulting from symptomatic neuromas within the amputation stumps. When conservative measures fail to address these symptoms, two contemporary surgical approaches to treat symptomatic neuromas have become the most popular. Targeted muscle reinnervation (TMR) is a procedure which involves transferring the injured proximal nerve stump into a terminal nerve branch entering muscle, such that the axons from the proximal nerve stump will regenerate into the muscle and thereby prevent neuroma recurrence. Regenerative peripheral nerve interfaces (RPNIs) are muscle grafts placed on the proximal nerve stumps that serve as targets for the regenerating axons from the proximal nerve stumps.

While TMR and RPNIs have demonstrated promise for the treatment of symptomatic neuromas, prospective comparative data comparing outcomes with these two approaches is lacking.

The investigators have recently developed a novel approach to treat symptomatic neuromas that provides vascularized, denervated muscle targets (VDMTs) for the axons regenerating from the severed proximal nerve stump to reinnervate. This is accomplished by islandizing a segment of muscle on its blood supply and ensuring complete denervation prior to implanting the neighboring transected nerve stump into this muscle. VDMTs offer theoretical benefits in comparison to RPNIs and TMR that the investigators also aim to test in the proposed study.

The investigators' objective is to enroll amputees with symptomatic neuromas into a prospective study in which amputees will be randomized to undergo TMR, RPNI, or VDMT and subsequently monitored for pain and disability for 1-year post-operatively. The investigators' specific aims are as follows: 1) Test the hypothesis that VDMTs are more effective than TMR and RPNIs with regards to treating pain and disability associated with symptomatic neuromas; 2) Provide the first level one, prospective data directly comparing the efficacy of TMR and RPNIs.

Extremity amputations are common operations both in the United States and other areas of the world. It is estimated that there are nearly 2 million adults living in the United States alone. Etiologies for extremity amputation are diverse but the most common indications include complications of type 2 diabetes, non-diabetic peripheral vascular disease, trauma, and oncologic conditions. Given the increasing prevalence of several of these pathologies, conservative estimates suggest that the population of people living with an amputated limb will likely double within the next several decades.

Patients who undergo limb amputation are at significant risk of developing chronic neuropathic pain as a result of symptomatic neuroma formation, due in large part to the abundance of sizeable nerves within the extremities that are necessarily transected as part of the procedure. There are two distinct forms of pain experienced by patients who have undergone major extremity amputations. Residual limb pain is the more straightforward form of post-amputation pain attributable to neuroma formation within the amputation stump. Following peripheral nerve transection, axons regenerating from the proximal stump tend to form aggregates of disorganized neural growth called neuromas. Some neuromas will produce severe, intractable pain causing significant impairment in prosthetic fit and function, activities of daily living, and quality of life. Some estimates place the prevalence of residual limb pain attributable to neuroma formation as high as 75%. The other form of pain is known as phantom limb pain. While the underpinnings of phantom limb pain are the subject of ongoing debate, it is thought by many to arise from chronic stimulation of the cerebral cortex with painful inputs from peripheral neuromas, leading to unpredictable and poorly characterized reorganization of the cortex. Informed estimates of phantom limb pain prevalence as high as 85% have been reported. Successful prevention and treatment of symptomatic neuromas in the setting of limb amputation is therefore of paramount importance given the central role in the pathogenesis of chronic post-amputation limb pain encompassing both residual limb pain and phantom limb pain.

Treatment options for chronic post amputation pain caused by symptomatic neuromas are diverse. Medical options for both phantom limb pain and residual limb pain have been met with limited success. Despite the widespread use, the utility of neuromodulating medications, such as gabapentin, has been called into question by recent large scale meta-analyses that failed to demonstrate meaningful improvements. Neurotoxins, such as botulinum toxin, have also been studied and found to offer limited, if any, pain resolution.

One of the most commonly used surgical approaches to treat and prevent symptomatic neuromas involves burying the proximal nerve stump into nearby muscle. There is a widely-held misconception that burying a proximal nerve stump into muscle will prevent a neuroma from forming. However, elegant animal studies have proven that regeneration of a neuroma is virtually guaranteed because innervated muscle will not accept additional innervation from regenerating neurons.

In the past decade, two other surgical treatments for chronic post-amputation limb pain have come into vogue. Targeted muscle reinnervation (TMR) was initially pioneered as a means of providing intuitive control of advanced prostheses and only later observed to reduce neuroma pain. TMR involves transferring the proximal nerve stump of the injured nerve into a nearby distal motor branch. Early results are promising. A recently published randomized, controlled trial demonstrated the superiority of the TMR approach over the 'bury in muscle' approach, so much so that the trial concluded prematurely due to the superiority of the TMR compared to the historical technique.

The other recently developed and widely popularized option for surgical treatment of chronic post-amputation limb pain involves creation of a regenerative peripheral nerve interface (RPNI). Similar to TMR, the RPNI was initially conceived as a method to provide an interface with an advanced neuroprosthetic prior to being employed as a treatment strategy for neuromas. RPNIs are muscle grafts that are coapted to the ends of severed proximal nerve stumps. This technique has gained popularity because of its technical simplicity and promising early clinical data. In contrast to the 'bury in muscle' approach, RPNIs are denervated at the time of harvest and have been shown to accept reinnervation via direct neurotization from the proximal nerve stump.

To address possible limitations of the strategies described above, the investigators propose using muscle targets similar to RPNIs but maintaining vascularity - a vascularized, denervated muscle target (VDMT). This is accomplished by raising a portion of muscle on a vascular leash in proximity to the transected nerve. Perforating branches from larger blood vessels that perfuse adjacent muscle can be found in abundance throughout the extremities. Any nerves traveling with the vascular leashes will be divided to ensure complete denervation of the muscle. Therefore, VDMTs will be receptive to reinnervation from the implanted proximal nerve stump, maintain vascularity such that the VDMTs can be large enough to supply an abundance of sensory receptors (spindle cells, Golgi apparati, etc) to accept regenerating axons, and avoid the use of a nerve coaptation. In short, the VDMT offers possible enhancements to the surgical techniques currently in use.

In terms of surgical outcomes, there is a robust body of data surrounding the TMR and RPNI operations, with some more recent reports providing pre- and post-operative pain scores for the individual operations. With the exception of one study that prospectively compared TMR to the historical gold standard of neuroma excision and implantation into surrounding tissue, there is a startling lack of prospective data on pain outcomes. Furthermore, the investigators are not aware of prospective, head-to-head comparative data for RPNI vs TMR. Robust, prospective, comparative data is now needed to validate the VDMT approach and assess its efficacy in comparison to the other established techniques.

It is of prime importance to surgeons who perform extremity amputations (eg orthopedic surgeons, vascular surgeons, trauma surgeons, plastic surgeons, and podiatrists) as well as those who perform salvage procedures for post-amputation extremity pain to understand the potential of these operations in treating this pain. Physicians are still lacking evidence-based treatment guidelines. With the generation of this data, surgeons and patients can make more informed decisions about which operative intervention provides the highest likelihood of durable, significant pain relief.

Surgical Treatments for Neuroma Pain in Amputees

A Randomized Trial Comparing Surgical Treatments for Neuroma Pain in Amputees

Pain score will be assessed using the numerical pain score (0-10) with 0 representing no pain and 10 representing the worst pain.

The Plastic Surgery Foundation

Johns Hopkins University

Standard Post-Amputation Surgical Care: Briefly, the transected nerves will be blindly tucked into surrounding bulky soft tissue to protect the nerve ends before the wound is closed.

Briefly, each transected nerve is identified after amputation using 6-0 Prolene suture and is dissected proximally for length. With minimal dissection, a nerve stimulator is used to identify functional motor nerve branches. Near the point where the motor branch enters the muscle, the motor nerve branch is transected and an end-to-end coaptation is performed with a nearby tagged amputated nerve.

Briefly, a muscle graft (usually from the amputated limb) is wrapped around the clean ends of the transected nerve(s).

Targeted Muscle Re-innervation involves re-routing transected nerve ends to functional motor nerves proximal to the site of amputation.

Targeted Muscle Re-innervation

Regenerative Peripheral Nerve Interface involves placing transected nerve ends in harvested muscle grafts.

Regenerative Peripheral Nerve Interface

Standard post-amputation surgical care involves placing transected nerve ends into muscle/soft tissue proximal to the site of amputation.

Standard Post-Amputation Surgical Care

Deborah Noble

The purpose of this study is to analyze the efficacy of novel interventions in post-amputation surgical care (specifically Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interface) on post-amputation pain and functional outcomes at the time of amputation. These novel interventions have been shown to be successful in treating the downstream effects of amputations (pain, phantom limb pain, neuroma pain, etc.), but has not been studied in a randomized manner at the time of amputation.

The investigators plan a randomized control trial of all eligible patients undergoing major limb amputation at Parkland Memorial Hospital. Eligible patients undergoing an amputation will be consented for all possible interventions and randomized to either receive Targeted Muscle Re-Innervation (TMR), Regenerative Peripheral Nerve Interface (RPNI), or standard post-amputation surgical care at the time of their operation. Key pre-operative data including patient sex, age, BMI, past medical history, past surgical history, medications, allergies, social history, social support systems, exposure to narcotic medication, and reason for amputation will be analyzed. Intra-operatively, patients randomized to the treatment arm will receive TMR or RPNI and the transected nerve ends addressed will be recorded. Post-operative data that will be recorded include hospital stay, complications related to the procedure, complications leading to reoperation, functional results, need for pain medication, incidence of phantom limb pain, incidence of painful neuromas, length of follow-up, and all adverse events/complications. Analyses will be conducted using data obtained from patient medical records from the Parkland Health \& Hospital System.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Focused Ultrasound Treatment of Stump Neuromas for the Relief of Chronic Post-Amputation Neuropathic Pain	NCT03255395	Phantom Limb Pa... Residual Limbs Amputation	Magnetic resona...	18 Years -	Rambam Health Care Campus
Surgical Treatments for Postamputation Pain	NCT05009394	Residual Limb P... Amputation Neur... Phantom Limb Pa... Pain, Neuropath... Pain, Nerve	Targeted Muscle... Regenerative Pe... Standard neurom...	18 Years -	Center for Bionics and Pain Research
Focused Ultrasound Treatment of Stump Neuromas for the Relief of Chronic Post-Amputation Neuropathic Pain	NCT03255395	Phantom Limb Pa... Residual Limbs Amputation	Magnetic resona...	18 Years -	Rambam Health Care Campus
Postoperative Peripheral Nerve Stimulation for Management of Post-amputation Pain	NCT03484429	Phantom Limb Pa... Postoperative P... Neuroma Acute Pain Chronic Pain Residual Limbs Amputation	Peripheral nerv... Standard Medica...	18 Years -	Hunter Holmes Mcguire Veteran Affairs Medical Center
Postoperative Peripheral Nerve Stimulation for Management of Post-amputation Pain	NCT03484429	Phantom Limb Pa... Postoperative P... Neuroma Acute Pain Chronic Pain Residual Limbs Amputation	Peripheral nerv... Standard Medica...	18 Years -	Hunter Holmes Mcguire Veteran Affairs Medical Center
Surgical Treatments for Neuroma Pain in Amputees	NCT04204668	Pain, Neuropath... Amputation Neur... Phantom Limb Pa...	TMR RPNI VDMT	18 Years -	Johns Hopkins University
Effect of Prophylactic TMR and RPNI on Neuroma and Phantom Limb Pain	NCT05344261	Amputation Neuroma Amputat... Phantom Limb Pa... Residual Limbs	Targeted Muscle... Regenerative Pe... Standard Post-A...	18 Years -	University of Texas Southwestern Medical Center
Postoperative Peripheral Nerve Stimulation for Management of Post-amputation Pain	NCT03484429	Phantom Limb Pa... Postoperative P... Neuroma Acute Pain Chronic Pain Residual Limbs Amputation	Peripheral nerv... Standard Medica...	18 Years -	Hunter Holmes Mcguire Veteran Affairs Medical Center
C-RFA of Residual Limb Neuroma	NCT04538417	Phantom Limb Pa... Neuroma Amputat...	Cooled Radiofre...	18 Years -	University of Utah
Effect of Prophylactic TMR and RPNI on Neuroma and Phantom Limb Pain	NCT05344261	Amputation Neuroma Amputat... Phantom Limb Pa... Residual Limbs	Targeted Muscle... Regenerative Pe... Standard Post-A...	18 Years -	University of Texas Southwestern Medical Center

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